bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti–PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
Authors: Sánchez-Paulete Alfonso R. , Cueto Francisco J. , Martínez-López María , Labiano Sara , Morales-Kastresana Aizea , Rodríguez-Ruiz María E. , Jure-Kunkel Maria , Azpilikueta Arantza , Aznar M. Angela , Quetglas José I. , Sancho David , Melero Ignacio
Published: March 2024

Abstract
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3−/− mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti–PD-1 mAbs. Batf3−/− mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti–CD137- and anti–PD-1–mediated immunostimulation in tumor therapy against B16-ovalbumin–derived melanomas, whereas this function was lost in Batf3−/− mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.

Significance: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti–PD-1 and anti-CD137 immunostimulatory mAbs. Cancer Discov; 6(1); 71–9. ©2015 AACR.

See related commentary by Robert-Tissot and Speiser, p. 17.

This article is highlighted in the In This Issue feature, p. 1
Data from Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer
Authors: Haricharan Svasti , Punturi Nindo , Singh Purba , Holloway Kimberly R. , Anurag Meenakshi , Schmelz Jacob , Schmidt Cheryl , Lei Jonathan T. , Suman Vera , Hunt Kelly , Olson John A. , Hoog Jeremy , Li Shunqiang , Huang Shixia , Edwards Dean P. , Kavuri Shyam M. , Bainbridge Matthew N. , Ma Cynthia X. , Ellis Matthew J.
Published: March 2024

Abstract
Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care.

Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1047
Data from Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
Authors: Sotillo Elena , Barrett David M. , Black Kathryn L. , Bagashev Asen , Oldridge Derek , Wu Glendon , Sussman Robyn , Lanauze Claudia , Ruella Marco , Gazzara Matthew R. , Martinez Nicole M. , Harrington Colleen T. , Chung Elaine Y. , Perazzelli Jessica , Hofmann Ted J. , Maude Shannon L. , Raman Pichai , Barrera Alejandro , Gill Saar , Lacey Simon F. , Melenhorst Jan J. , Allman David , Jacoby Elad , Fry Terry , Mackall Crystal , Barash Yoseph , Lynch Kristen W. , Maris John M. , Grupp Stephan A. , Thomas-Tikhonenko Andrei
Published: March 2024

Abstract
The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor–armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms.

Significance: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR.

See related commentary by Jackson and Brentjens, p. 1238.

This article is highlighted in the In This Issue feature, p. 1225
Data from Dissection of the Major Hematopoietic Quantitative Trait Locus in Chromosome 6q23.3 Identifies miR-3662 as a Player in Hematopoiesis and Acute Myeloid Leukemia
Authors: Maharry Sophia E. , Walker Christopher J. , Liyanarachchi Sandya , Mehta Sujay , Patel Mitra , Bainazar Maryam A. , Huang Xiaomeng , Lankenau Malori A. , Hoag Kevin W. , Ranganathan Parvathi , Garzon Ramiro , Blachly James S. , Guttridge Denis C. , Bloomfield Clara D. , de la Chapelle Albert , Eisfeld Ann-Kathrin
Published: March 2024

Abstract
Chromosomal aberrations and multiple genome-wide association studies (GWAS) have established a major hematopoietic quantitative trait locus in chromosome 6q23.3. The locus comprises an active enhancer region, in which some of the associated SNPs alter transcription factor binding. We now identify miR-3662 as a new functional driver contributing to the associated phenotypes. The GWAS SNPs are strongly associated with higher miR-3662 expression. Genome editing of rs66650371, a three-base-pair deletion, suggests a functional link between the SNP genotype and the abundance of miR-3662. Increasing miR-3662′s abundance increases colony formation in hematopoietic progenitor cells, particularly the erythroid lineage. In contrast, miR-3662 is not expressed in acute myeloid leukemia cells, and its overexpression has potent antileukemic effects in vitro and in vivo. Mechanistically, miR-3662 directly targets NF-κB–mediated transcription. Thus, miR-3662 is a new player of the hematopoietic 6q23.3 locus.

Significance: The characterization of miR-3662 has identified a new actor in the prominent hematopoietic quantitative trait locus in chromosome 6q23.3. The mechanistic insights into miR-3662′s function may reveal novel or only partially known pathways for normal and malignant hematopoietic cell proliferation. Cancer Discov; 6(9); 1036–51. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 932
Data from The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
Authors: Reiff Sean D. , Mantel Rose , Smith Lisa L. , Greene J.T. , Muhowski Elizabeth M. , Fabian Catherine A. , Goettl Virginia M. , Tran Minh , Harrington Bonnie K. , Rogers Kerry A. , Awan Farrukh T. , Maddocks Kami , Andritsos Leslie , Lehman Amy M. , Sampath Deepa , Lapalombella Rosa , Eathiraj Sudharshan , Abbadessa Giovanni , Schwartz Brian , Johnson Amy J. , Byrd John C. , Woyach Jennifer A.
Published: March 2024

Abstract
Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.

Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300–15. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
Data from Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment
Authors: Sukumaran Sujita , Watanabe Norihiro , Bajgain Pradip , Raja Kanchana , Mohammed Somala , Fisher William E. , Brenner Malcolm K. , Leen Ann M. , Vera Juan F.
Published: March 2024

Abstract
The adoptive transfer of chimeric antigen receptor (CAR)–modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in “on-target, off-tumor” toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize prostate stem cell antigen, TGFβ, and IL4, and whose endodomains recapitulate physiologic T-cell signaling by providing signals for activation, costimulation, and cytokine support, produce potent antitumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g., PD-L1, IL10, and IL13).

Significance: This proof-of-concept study demonstrates how sophisticated engineering approaches can be utilized to both enhance the antitumor efficacy and increase the safety profile of transgenic T cells by incorporating a combination of receptors that ensure that cells are active exclusively at the tumor site. Cancer Discov; 8(8); 972–87. ©2018 AACR.

See related commentary by Achkova and Pule, p. 918.

This article is highlighted in the In This Issue feature, p. 899
Data from Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models
Authors: Mata Melinda , Gerken Claudia , Nguyen Phuong , Krenciute Giedre , Spencer David M. , Gottschalk Stephen
Published: March 2024

Abstract
Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)–binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2–CARζ and a MyD88/CD40–based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2–CAR.CD28ζ. HER2ζ.iCO T cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T cells in vivo. Thus, expressing MyD88/CD40–based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.

Significance: Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion. Cancer Discov; 7(11); 1306–19. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1201
Data from Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy
Authors: Hinze Laura , Labrosse Roxane , Degar James , Han Teng , Schatoff Emma M. , Schreek Sabine , Karim Salmaan , McGuckin Connor , Sacher Joshua R. , Wagner Florence , Stanulla Martin , Yuan Chen , Sicinska Ewa , Giannakis Marios , Ng Kimmie , Dow Lukas E. , Gutierrez Alejandro
Published: March 2024

Abstract
Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin–independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream (APC or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in APC or β-catenin–mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in APC or β-catenin–mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy.
Significance:
Solid tumors are thought to be asparaginase-resistant via de novo asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer.

See related commentary by Davidsen and Sullivan, p. 1632.

This article is highlighted in the In This Issue feature, p. 1611
Data from Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD+ to Potentiate the Metabolic Lethality of Alkylating Chemotherapy in IDH-Mutant Tumor Cells
Authors: Nagashima Hiroaki , Lee Christine K. , Tateishi Kensuke , Higuchi Fumi , Subramanian Megha , Rafferty Seamus , Melamed Lisa , Miller Julie J. , Wakimoto Hiroaki , Cahill Daniel P.
Published: March 2024

Abstract
NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation.
Significance:
Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit.

See related commentary by Pirozzi and Yan, p. 1629.

This article is highlighted in the In This Issue feature, p. 1611
Data from Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia
Authors: Pei Shanshan , Pollyea Daniel A. , Gustafson Annika , Stevens Brett M. , Minhajuddin Mohammad , Fu Rui , Riemondy Kent A. , Gillen Austin E. , Sheridan Ryan M. , Kim Jihye , Costello James C. , Amaya Maria L. , Inguva Anagha , Winters Amanda , Ye Haobin , Krug Anna , Jones Courtney L. , Adane Biniam , Khan Nabilah , Ponder Jessica , Schowinsky Jeffrey , Abbott Diana , Hammes Andrew , Myers Jason R. , Ashton John M. , Nemkov Travis , D'Alessandro Angelo , Gutman Jonathan A. , Ramsey Haley E. , Savona Michael R. , Smith Clayton A. , Jordan Craig T.
Published: March 2024

Abstract
Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis.
Significance:
Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.
Data from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer
Authors: Amodio Vito , Yaeger Rona , Arcella Pamela , Cancelliere Carlotta , Lamba Simona , Lorenzato Annalisa , Arena Sabrina , Montone Monica , Mussolin Benedetta , Bian Yu , Whaley Adele , Pinnelli Marika , Murciano-Goroff Yonina R. , Vakiani Efsevia , Valeri Nicola , Liao Wei-Li , Bhalkikar Anuja , Thyparambil Sheeno , Zhao Hui-Yong , de Stanchina Elisa , Marsoni Silvia , Siena Salvatore , Bertotti Andrea , Trusolino Livio , Li Bob T. , Rosen Neal , Di Nicolantonio Federica , Bardelli Alberto , Misale Sandra
Published: March 2024

Abstract
Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer.
Significance:
The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.

See related commentary by Koleilat and Kwong, p. 1094.

This article is highlighted in the In This Issue feature, p. 1079
Data from Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers
Authors: Song Xinxin , Zhou Zhuan , Li Hongchun , Xue Yifan , Lu Xinghua , Bahar Ivet , Kepp Oliver , Hung Mien-Chie , Kroemer Guido , Wan Yong
Published: March 2024

Abstract
Despite widespread utilization of immunotherapy, treating immune-cold tumors has proved to be a challenge. Here, we report that expression of the immune checkpoint molecule B7-H4 is prevalent among immune-cold triple-negative breast cancers (TNBC), where its expression inversely correlates with that of PD-L1. Glycosylation of B7-H4 interferes with its interaction/ubiquitination by AMFR, resulting in B7-H4 stabilization. B7-H4 expression inhibits doxorubicin-induced cell death through the suppression of eIF2α phosphorylation required for calreticulin exposure vis-à-vis the cancer cells. NGI-1, which inhibits B7-H4 glycosylation causing its ubiquitination and subsequent degradation, improves the immunogenic properties of cancer cells treated with doxorubicin, enhancing their phagocytosis by dendritic cells and their capacity to elicit CD8+ IFNγ-producing T-cell responses. In preclinical models of TNBC, a triple combination of NGI-1, camsirubicin (a noncardiotoxic doxorubicin analogue) and PD-L1 blockade was effective in reducing tumor growth. Collectively, our findings uncover a strategy for targeting the immunosuppressive molecule B7-H4.
Significance:
This work unravels the regulation of B7-H4 stability by ubiquitination and glycosylation, which affects tumor immunogenicity, particularly regarding immune-cold breast cancers. The inhibition of B7-H4 glycosylation can be favorably combined with immunogenic chemotherapy and PD-L1 blockade to achieve superior immuno-infiltration of cold tumors, as well as improved tumor growth control.

See related commentary by Pearce and Läubli, p. 1789.

This article is highlighted in the In This Issue feature, p. 1775
Data from Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective In Vivo without Systemic Immune Activation
Authors: Kamata-Sakurai Mika , Narita Yoshinori , Hori Yuji , Nemoto Takayuki , Uchikawa Ryo , Honda Masaki , Hironiwa Naoka , Taniguchi Kenji , Shida-Kawazoe Meiri , Metsugi Shoichi , Miyazaki Taro , Wada Naoko A. , Ohte Yuki , Shimizu Shun , Mikami Hirofumi , Tachibana Tatsuhiko , Ono Natsuki , Adachi Kenji , Sakiyama Tetsushi , Matsushita Tomochika , Kadono Shojiro , Komatsu Shun-ichiro , Sakamoto Akihisa , Horikawa Sayuri , Hirako Ayano , Hamada Koki , Naoi Sotaro , Savory Nasa , Satoh Yasuko , Sato Motohiko , Noguchi Yuki , Shinozuka Junko , Kuroi Haruka , Ito Ami , Wakabayashi Tetsuya , Kamimura Masaki , Isomura Fumihisa , Tomii Yasushi , Sawada Noriaki , Kato Atsuhiko , Ueda Otoya , Nakanishi Yoshito , Endo Mika , Jishage Kou-ichi , Kawabe Yoshiki , Kitazawa Takehisa , Igawa Tomoyuki
Published: March 2024

Abstract
Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor-selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad antitumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy.
Significance:
Reported CD137 agonists suffer from either systemic toxicity or limited efficacy against antigen-specific cancers. STA551, an antibody designed to agonize CD137 only in the presence of extracellular ATP, inhibited tumor growth in a broad variety of cancer models without any systemic toxicity or dependence on antigen expression.

See related commentary by Keenan and Fong, p. 20.

This article is highlighted in the In This Issue feature, p. 1
Data from Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition
Authors: Schatoff Emma M. , Goswami Sukanya , Zafra Maria Paz , Foronda Miguel , Shusterman Michael , Leach Benjamin I. , Katti Alyna , Diaz Bianca J. , Dow Lukas E.
Published: March 2024

Abstract
The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the mutation cluster region physically engage the destruction complex and suppress the WNT transcriptional program, while APC variants with early truncations (e.g., ApcMin) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response.
Significance:
This study reveals how subtle changes to the mutations in a critical colorectal tumor suppressor, APC, influence the cellular response to a targeted therapy. It underscores how investigating the specific genetic alterations that occur in human cancer can identify important biological mechanisms of drug response and resistance.

This article is highlighted in the In This Issue feature, p. 1325
Data from Protumor Steering of Cancer Inflammation by p50 NF-κB Enhances Colorectal Cancer Progression
Authors: Porta Chiara , Ippolito Alessandro , Consonni Francesca Maria , Carraro Lorenzo , Celesti Giuseppe , Correale Carmen , Grizzi Fabio , Pasqualini Fabio , Tartari Silvia , Rinaldi Maurizio , Bianchi Paolo , Balzac Fiorella , Vetrano Stefania , Turco Emilia , Hirsch Emilio , Laghi Luigi , Sica Antonio
Published: March 2024

Abstract
Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-κB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven ApcMin mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50–/– mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo. The inflammatory profile supporting tumor resistance in colons from p50–/– tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8+ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50+ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention. Cancer Immunol Res; 6(5); 578–93. ©2018 AACR.
Data from Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy
Authors: Berkeley Robert A. , Steele Lynette P. , Mulder Aat A. , van den Wollenberg Diana J.M. , Kottke Timothy J. , Thompson Jill , Coffey Matthew , Hoeben Rob C. , Vile Richard G. , Melcher Alan , Ilett Elizabeth J.
Published: March 2024

Abstract
Immunotherapy is showing promise for otherwise incurable cancers. Oncolytic viruses (OVs), developed as direct cytotoxic agents, mediate their antitumor effects via activation of the immune system. However, OVs also stimulate antiviral immune responses, including the induction of OV-neutralizing antibodies. Current dogma suggests that the presence of preexisting antiviral neutralizing antibodies in patients, or their development during viral therapy, is a barrier to systemic OV delivery, rendering repeat systemic treatments ineffective. However, we have found that human monocytes loaded with preformed reovirus–antibody complexes, in which the reovirus is fully neutralized, deliver functional replicative reovirus to tumor cells, resulting in tumor cell infection and lysis. This delivery mechanism is mediated, at least in part, by antibody receptors (in particular FcγRIII) that mediate uptake and internalization of the reovirus/antibody complexes by the monocytes. This finding has implications for oncolytic virotherapy and for the design of clinical OV treatment strategies. Cancer Immunol Res; 6(10); 1161–73. ©2018 AACR.
Data from Association Studies of Fcγ Receptor Polymorphisms with Outcome in HER2+ Breast Cancer Patients Treated with Trastuzumab in NCCTG (Alliance) Trial N9831
Authors: Norton Nadine , Olson Rebecca M. , Pegram Mark , Tenner Kathleen , Ballman Karla V. , Clynes Raphael , Knutson Keith L. , Perez Edith A.
Published: March 2024

Abstract
Patients with HER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared with patients treated with chemotherapy alone. Polymorphisms within FCGR2A and FCGR3A are associated with binding affinity of natural killer cells to the IgG1 portion of trastuzumab, and a polymorphism in FCGR2B (I232T) is associated with impaired regulatory activity. The association of these polymorphisms with clinical response among trastuzumab-treated patients is equivocal, with both positive and negative associations. We performed genotyping analysis on the FCGR3A V158F, FCGR2A R131H, and FCGR2B I232T polymorphisms in 1,325 patients from the N9831 clinical trial. Patients in arm A (N = 419) received chemotherapy only. Patients in arms B (N = 469) and C (N = 437) were treated with chemotherapy and trastuzumab (sequentially in arm B and concurrently in arm C). Using log-rank test and Cox proportional hazard models, we compared disease-free survival (DFS) among genotypic groups within pooled arms B/C. We found no differences in DFS between trastuzumab-treated patients who had the FCGR3A 158 V/V and/or FCGR2A 131 H/H high-affinity genotypes and patients without those genotypes. Furthermore, there was no significant interaction between FCGR3A and FCGR2A and treatment. However, there was a difference in DFS for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (P < 0.001), compared with the T carriers who did not (P = 0.81). The interaction between FCGR2B genotype and treatment was statistically significant (P = 0.03). Our analysis did not reveal an association between FcγR high-affinity genotypes and outcomes. However, it seems that the FCGR2B inhibitory gene may be predictive of adjuvant trastuzumab benefit. Cancer Immunol Res; 2(10); 962–9. ©2014 AACR.
Data from Caspase-1 from Human Myeloid-Derived Suppressor Cells Can Promote T Cell–Independent Tumor Proliferation
Authors: Zeng Qi , Fu Juan , Korrer Michael , Gorbounov Mikhail , Murray Peter J. , Pardoll Drew , Masica David L. , Kim Young J.
Published: March 2024

Abstract
Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell–independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/– MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1–dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo, growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell–depleted conditions. Adoptive transfer of wild-type Gr-1+CD11b+ MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor-intrinsic MyD88-dependent carcinogenesis. In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell–independent mediator of tumor proliferation. Cancer Immunol Res; 6(5); 566–77. ©2018 AACR.
Data from MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells
Authors: Vella Laura J. , Pasam Anupama , Dimopoulos Nektaria , Andrews Miles , Knights Ashley , Puaux Anne-Laure , Louahed Jamila , Chen Weisan , Woods Katherine , Cebon Jonathan S.
Published: March 2024

Abstract
Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4+ or CD8+ T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings. Cancer Immunol Res; 2(4); 351–60. ©2014 AACR.
Data from GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model
Authors: Sabharwal Simran S. , Rosen David B. , Grein Jeff , Tedesco Dana , Joyce-Shaikh Barbara , Ueda Roanna , Semana Marie , Bauer Michele , Bang Kathy , Stevenson Christopher , Cua Daniel J. , Zúñiga Luis A.
Published: March 2024

Abstract
GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8+ T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8+ T-cell metabolism. We found activated, GITR-treated CD8+ T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) in vitro. Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an in vitro model of PD-L1–induced CD8+ T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti–PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymph node (DLN) CD8+ T cells ex vivo, as well as basal glycolysis in DLN and spare glycolytic capacity in tumor CD8+ T cells. DLN in GITR-treated mice showed significant upregulation of proliferative gene expression compared with controls. These data show that GITR agonism increases metabolism to support CD8+ T-cell proliferation and effector function in vivo, and that understanding the mechanism of action of agonistic GITR antibodies is crucial to devising effective combination therapies. Cancer Immunol Res; 6(10); 1199–211. ©2018 AACR.
Data from BRAF Inhibition Alleviates Immune Suppression in Murine Autochthonous Melanoma
Authors: Steinberg Shannon M. , Zhang Peisheng , Malik Brian T. , Boni Andrea , Shabaneh Tamer B. , Byrne Katelyn T. , Mullins David W. , Brinckerhoff Constance E. , Ernstoff Marc S. , Bosenberg Marcus W. , Turk Mary Jo
Published: March 2024

Abstract
A growing body of evidence suggests that BRAF inhibitors, in addition to their acute tumor growth–inhibitory effects, can also promote immune responses to melanoma. The present study aimed to define the immunologic basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4+Foxp3+ regulatory T cells (Treg) and CD11b+Gr1+ myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8+ effector T cells. In PLX4720-treated mice, the intratumoral Treg populations decreased significantly, demonstrating enhanced apopotosis. CD11b+ myeloid cells from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma and liberates host-adaptive antitumor immunity. Cancer Immunol Res; 2(11); 1044–50. ©2014 AACR.
Data from A Blueprint to Advance Colorectal Cancer Immunotherapies
Authors: Le Dung T. , Hubbard-Lucey Vanessa M. , Morse Michael A. , Heery Christopher R. , Dwyer Andrea , Marsilje Thomas H. , Brodsky Arthur N. , Chan Emily , Deming Dustin A. , Diaz Luis A. , Fridman Wolf H. , Goldberg Richard M. , Hamilton Stanley R. , Housseau Franck , Jaffee Elizabeth M. , Kang S. Peter , Krishnamurthi Smitha S. , Lieu Christopher H. , Messersmith Wells , Sears Cynthia L. , Segal Neil H. , Yang Arvin , Moss Rebecca A. , Cha Edward , O'Donnell-Tormey Jill , Roach Nancy , Davis Anjelica Q. , McAbee Keavy , Worrall Sharyn , Benson Al B.
Published: March 2024

Abstract
Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability–high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942–9. ©2017 AACR.
Data from The Inhibitory Signaling Receptor Protocadherin-18 Regulates Tumor-Infiltrating CD8+ T-cell Function
Authors: Frey Alan B.
Published: March 2024

Abstract
Cancers are infiltrated with antitumor CD8+ T cells that arise during tumor growth, but are defective in effector phase functions because of the suppressive microenvironment. The reactivation of TILs can result in tumor destruction, showing that lytic dysfunction in CD8+ tumor-infiltrating lymphocytes (TIL) permits tumor growth. Like all memory T cells, TILs express inhibitory signaling receptors (aka checkpoint inhibitor molecules) that downregulate TCR-mediated signal transduction upon TIL interaction with cells expressing cognate ligands, thereby restricting cell activation and preventing the effector phase. Previously, we identified a novel murine CD8+ TIL inhibitory signaling receptor, protocadherin-18, and showed that it interacts with p56lck kinase to abrogate proximal TCR signaling. Here, we show that TILs from mice deleted in protocadherin-18 had enhanced antitumor activity and that coblockade of PD-1 and protocadherin-18 in wild-type mice significantly enhanced TIL effector phase function. These results define an important role for protocadherin-18 in antitumor T-cell activity. Cancer Immunol Res; 5(10); 920–8. ©2017 AACR.
Data from Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach
Authors: Johanns Tanner M. , Ward Jeffrey P. , Miller Christopher A. , Wilson Courtney , Kobayashi Dale K. , Bender Diane , Fu Yujie , Alexandrov Anton , Mardis Elaine R. , Artyomov Maxim N. , Schreiber Robert D. , Dunn Gavin P.
Published: March 2024

Abstract
The “cancer immunogenomics” paradigm has facilitated the search for tumor-specific antigens over the last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific “neoantigens” in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. GL261 and SMA-560 harbored 4,932 and 2,171 nonsynonymous exome mutations, respectively, of which less than half were expressed. To establish the immunogenicities of H-2Kb and H-2Db candidate neoantigens, we assessed the ability of the epitopes predicted in silico to be the highest affinity binders to activate tumor-infiltrating T cells harvested from GL261 and SMA-560 tumors. Using IFNγ ELISPOT, we confirmed H-2Db–restricted Imp3D81N (GL261) and Odc1Q129L (SMA-560) along with H-2Kb–restricted E2f8K272R (SMA-560) as endogenous tumor-specific neoantigens that are functionally immunogenic. Furthermore, neoantigen-specific T cells to Imp3D81N and Odc1Q129L were detected within intracranial tumors as well as cervical draining lymph nodes by tetramer analysis. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell–activating immunotherapeutic approaches in preclinical models of glioblastoma. Cancer Immunol Res; 4(12); 1007–15. ©2016 AACR.