Impact of microbiota specific circulating memory T cells in response to immunotherapy.
Authors: Gattazzo Federica , Birebent Roxanne , Lebhar Isabelle , Xiberras Marie , Marques Mathias , Reni Anna , Flament Caroline , Bonato Adele , Belluomini Lorenzo , Chanfreau-Paris Hugo , Carrier Agathe , Besse Benjamin , Albiges Laurence , Ramon Jordi , Parisi Claudia , Deroussent Marie , Berthier Franck , Silva Carolina Alves Costa , Derosa Lisa , Zitvogel Laurence 
Published: June 2024

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Background: The gut microbiota influences the cancer immune set point and response to immune checkpoint inhibitors (ICB), participating in the differentiation and function of T cells. We aimed to investigate the potential impact of microbiota-specific circulating memory T cells in cancer immunotherapy. Methods: NCT04567446 provided longitudinal blood samples (T0, before starting ICB until 1.5 months; T3, between 3 and 5.5 months) from patients with lung (NSCLC) and kidney (RCC) during ICB therapy (alone or combinations) in France. Different pools of harmful (ENTERO: Enteroclosterspp, Hungatella hathewayi, VEILLEG: Veillonella spp, Eggerthella lenta and KLEBC: Klebsiella pneumoniae, Escherichia coli, Fusobacterium nucleatum (Fn)) or single beneficial (Akkermansia spp. (Akk), Faecalibacterium prausnitzii ( Fp)) pasteurized bacteria (ppB) were used to stimulate whole blood sample (22h). The secretion of CXCL13, IL-17 (ELISA) and IFNg (VIDAS) was quantified at baseline and longitudinally to characterize memory TFH, TH17 and TH1 responses, respectively and analyze the effects of antibiotics. Progression-free survival (PFS), overall survival (OS) were assessed according to bacteria-specific T cell responses. Results: From Mar. 2023 to Jan. 2024, a total of 75 patients were screened and 39 patients enrolled in this analysis (54 assessed samples). Median age was 66yr, 72% were male, 74% had NSCLC, 26% had RCC and 78% were treated in first line. Median progression-free survival was 5.3 months (0.9-12.4); median overall-survival was 5.9 months (1.5-12.4). Firstly, we analyzed the 33 samples at baseline. 15% of patients harbored Akk-specific TFH memory responses and those patients with CXCL13 secretion superior to the median of the cohort tended to exhibit longer PFS (p=0.064) while 54% of patients harbored KLEBC TFH memory responses that were clinically irrelevant. 15% of patients harboring circulating Akk-specific TH1 memory responses had a shorter OS (p=0.055) while VEILLEG or KLEBC-specific TH1 responses detected in 24% and 42% cases were clinically irrelevant. 26/32 patients who did not show Akk-specific TH17 responses had a better OS. ATB tended to decrease bacteria-specific CXCL13 and IFNg responses but increased TH17 memory T cells. While boosting the systemic TH1 TCR tonus (IFNg secretion by fresh blood T cells stimulated with the positive control (mitogen)), ICB decreased the most prominent reactivities against KLEBC, VEILLEG or Akk, suggesting that bacteria-specific T cells may traffic to tumoral or intestinal locations. Conclusions: Although awaiting further validation and correlations with humoral IgG/A titers, circulating memory T cells against distinct commensals may be clinically relevant to predict benefit to immunotherapy, suggesting that such bacteria may invade tumor cells or share molecular homology with cancer antigens. Clinical trial information: NCT04567446 .