Abstract 1189: Modulation of the MSS and MSI colorectal cancer immune microenvironment with FOLFOX and FOLFIRI -/+ anti-PD-1 immunotherapy
Authors: Carlsen Lindsey , Pinho-Schwermann Maximilian , Zhang Leiqing , Elliott Andrew , Huntington Kelsey E. , MacDonald William J. , Verschleiser Brooke , Wu Laura Jinxuan , El-Deiry Wafik S. 
Published: March 2024

Abstract
Metastatic colorectal cancer (mCRC) is a deadly disease with a five-year survival rate of 14%. Most patients receive 5-FU (F) and folinic acid (FOL) combined with oxaliplatin (OX), irinotecan (IRI), or both (OXIRI). Immune checkpoint inhibitors (ICIs) are effective against microsatellite instable (MSI) tumors, but 95% of mCRC tumors are microsatellite stable (MSS) and ICI-resistant. Though the primary targets of 5-FU, irinotecan, and oxaliplatin are well-understood, their effects on the tumor microenvironment (TME) remain incompletely characterized. Chemotherapy-mediated immune stimulation in MSS CRC has been observed in preclinical models and clinical trials. We hypothesize that combination chemotherapy treatment modulates the immune microenvironment of CRC -/+ ICI, with differences across subtype and treatment regimen. Chemotherapy-dependent changes in cancer cell gene expression, PD-L1 levels, cytokine secretion, and T cell activation were measured using in vitro models of MSS and MSI CRC. A preliminary evaluation of spleen and tumor T cells and dendritic cells (DCs) in murine models of MSS and MSI CRC after immunotherapy -/+ chemotherapy was conducted. CD8+ T cells, DCs, PD-L1, CD69, and GM-CSF expression were measured in clinical specimens of chemotherapy-treated MSS mCRC patients. In MSS CRC, FOX increased GM-CSF and activated CD8+ T cells in vitro and activated splenic CD8+ and CD4+ T cells in vivo. FOX and FIRI suppressed an anti-PD-1-mediated enhancement of type 1 cDCs in the tumor in vivo. FOLFOX was associated with increased tumor CD8+ T cells and decreased GM-CSF in MSS mCRC biopsies. FIRI treatment increased PD-L1 in vitro. FOLFIRI was not associated with increased tumor CD8+ T cells in MSS mCRC biopsies. In MSI CRC, FOX increased tumor CD8+ T cells in vivo. Here, we elucidate novel effects of clinically relevant chemotherapy combinations on the TME in MSS and MSI CRC. These data point to a FOX-specific mechanism by which CD8+ T cell infiltration into MSS mCRC tumors is enhanced, but their activation is halted potentially by GM-CSF suppression and/or type 1 cDC depletion in the TME. These findings contribute to our understanding of the mechanisms of chemotherapy-dependent immune modulation and bring the field closer to harnessing these effects for therapeutic gain.
Citation Format: Lindsey Carlsen, Maximilian Pinho-Schwermann, Leiqing Zhang, Andrew Elliott, Kelsey E. Huntington, William J. MacDonald, Brooke Verschleiser, Laura Jinxuan Wu, Wafik S. El-Deiry. Modulation of the MSS and MSI colorectal cancer immune microenvironment with FOLFOX and FOLFIRI -/+ anti-PD-1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1189.