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Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection., Competing Interests: Competing interests: RF. Honoraria: Bayer, Astellas, Janssen, BMS, MSD, Ipsen, Pfizer, Merck, Astra Zeneca. MT. NoneMR-C. NoneLC-A. NoneLR. NoneNN. Honoraria: Merck, PfizerJ-MJ. NoneLB. NoneMN. NoneBE. Honoraria: Bristol:Myers Squibb, Ipsen, Oncorena, Pfizer. Consulting or Advisory Role : AVEO, Bristol:Myers Squibb, Ipsen, Oncorena, Pfizer. Research Funding : BMS France (Inst). Travel, Accommodations, Expenses : Bristol:Myers Squibb, Ipsen, MSDLC. NoneLA. Consulting or Advisory Role: Astellas Pharma (Inst), Bristol:Myers Squibb (Inst), Eisai (Inst), Ipsen (Inst), Janssen (Inst), MSD (Inst), Pfizer (Inst), Roche (Inst). Travel, Accommodations, Expenses: BMS, Ipsen, MSDNC. Scientific grants from Sanofi, BMS, Cytune Pharma, Scientist advisory board from Servier, lectures for AstraZeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Circulating senescent CD8 + T (T 8 sen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to immunotherapy in patients with advanced non-small cell lung cancer (aNSCLC). We aimed to better characterize T 8 sen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating T 8 sen cells were characterized by a higher expression of SA-βgal and the transcription factor T-bet, confirming their senescent status. Using whole virome profiling, cytomegalovirus (CMV) was the only virus associated with T 8 sen. CMV was necessary but not sufficient to explain high accumulation of T 8 sen (T 8 sen high status). In CMV + patients, the proportion of T 8 sen cells increased with cancer progression. Last, CMV-induced T 8 sen high phenotype but not CMV seropositivity itself was associated with worse progression-free and overall survival in patients treated with anti-PD-(L)1 therapy but not with chemotherapy. Overall, CMV is the unique viral driver of T 8 sen-driven resistance to anti-PD-(L)1 antibodies in patients with aNSCLC.

Background: Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood., Methods: 4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene Msh2, leading to a massive accumulation of mutations after serial passages of cells. Insertions/deletion events and mutation load were evaluated by whole exome sequencing. Mice bearing highly mutated MMRD tumor or parental tumors were treated with αPD-1 and tumor volume was monitored. Immune cell type abundance was dynamically assessed in the tumor microenvironment and the blood by flow cytometry. Neutrophils were depleted in mice using αLY6G antibody, and regulatory T (Treg) cell population was reduced with αCD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (αCTLA-4) antibodies. Patients with MMRD tumors treated with immune checkpoint blockade-based therapy were retrospectively identified and neutrophil-to-lymphocyte ratio (NLR) was evaluated and examined for correlation with clinical benefit., Results: By recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy., Conclusions: TIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation., Competing Interests: Competing interests: NC reports grants from Cytune Pharma, grants from BMS, grants from SANOFI, personal fees from AstraZeneca France, outside the submitted work. Other authors declare no conflict of interest with this work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Programmed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8 + PD-1 + and CD4 + PD-1 + in patients treated with immune checkpoint blockers (ICB) is unknown., Methods: The CD8 + PD-1 + to CD4 + PD-1 + ratio (PD-1-Expressing Ratio on Lymphocytes in a Systemic blood sample, or 'PERLS') was determined by cytometry in fresh whole blood from patients with aNSCLC before treatment with single-agent ICB targeting PD-1 or programmed cell death-ligand 1 (PD-L1 (discovery cohort). A PERLS cut-off was identified by log-rank maximization. Patients treated with ICB (validation cohort) or polychemotherapy (control cohort) were classified as PERLS+/- (above/below cut-off). Circulating immune cell phenotype and function were correlated with PERLS. A composite score (good, intermediate and poor) was determined using the combination of PERLS and senescent immune phenotype as previously described in aNSCLC., Results: In the discovery cohort (N=75), the PERLS cut-off was 1.91, and 11% of patients were PERLS+. PERLS + correlated significantly with median progression-free survival (PFS) of 9.63 months (95% CI 7.82 to not reached (NR)) versus 2.69 months (95% CI 1.81 to 5.52; p=0.03). In an independent validation cohort (N=36), median PFS was NR (95% CI 7.9 to NR) versus 2.00 months (95% CI 1.3 to 4.5; p=0.04) for PERLS + and PERLS-, respectively; overall survival (OS) followed a similar but non-significant trend. In the pooled cohort (N=111), PERLS + correlated significantly with PFS and OS. PERLS did not correlate with outcome in the polychemotherapy cohort. PERLS did not correlate with clinical characteristics but was significantly associated with baseline circulating naïve CD4 + T cells and the increase of memory T cells post-ICB treatment. Accumulation of memory T cells during treatment was linked to CD4 + T cell polyfunctionality. The composite score was evaluated in the pooled cohort (N=68). The median OS for good, intermediate and poor composite scores was NR (95% CI NR to NR), 8.54 months (95% CI 4.96 to NR) and 2.42 months (95% CI 1.97 to 15.5; p=0.001), respectively. The median PFS was 12.60 months (95% CI 9.63 to NR), 2.58 months (95% CI 1.74 to 7.29) and 1.76 months (95% CI 1.31 to 4.57; p<0.0001), respectively., Conclusions: Elevated PERLS, determined from a blood sample before immunotherapy, was correlated with benefit from PD-(L)1 blockers in aNSCLC., Competing Interests: Competing interests: BD: speakers bureaus or educational events from Roche, Pfizer, AstraZeneca, Chiesi, Amgen, Lilly; support for attending meetings and/or travel from AZ, Pfizer, Oxyvie. MN: no competing interest to declare, EA: support for attending meetings and/or travel from: Mundipharma; lectures and educational activities: Sanofi Genzymes. RF: senior advisory board meetings for MSD. LC, J-MJ, LB, JG, AD, F-XD: no competing interest to declare. LM: sponsored research: Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Stilla, Inivata. Consulting, advisory role: Roche Diagnostics, Takeda, Roche. Lectures and educational activities: Bristol Myers Squibb, Tecnofarma, Roche, Takeda. Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca. CC: no competing interest to declare. AM: senior advisory board meetings for MSD, BMS, AstraZeneca/Medimmune, Sanofi, Pfizer, Roche/Genentech, Merck Serono. Consulting services to Sanofi, Roche/Genentech. Speakers bureau of MSD, BMS, AstraZeneca/Medimmune, Sanofi, Roche/Genentech, Merck Serono. BB: sponsored research at Gustave Roussy Cancer Center 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. NC: sponsored research at Gustave Roussy Cancer Center from AstraZeneca, GSK, Roche, Sanofi, Cytune Pharma, Gilead, Servier., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors (ICI) have been validated as an effective new treatment strategy in several tumoral types including lung cancer. This remarkable shift in the therapeutic paradigm is in large part due to the duration of responses and long-term survival seen with ICI. However, despite this, the majority of cancer patients do not experience benefit from ICI. Even among patients who initially respond to ICI, disease progression may ultimately occur. Moreover, in some patients, these drugs may be associated with new patterns of progression such as pseudo-progression and hyper-progressive disease, and different toxicity profiles with immune-related adverse events. Therefore, the identification of predictive biomarkers may help to select those patients most likely to obtain a true benefit from these drugs, and avoid exposure to potential toxicity in patients who will not obtain clinical benefit, while also reducing the economic impact. In this review, we summarize current and promising potential predictive biomarkers of ICI in patients with non-small cell lung cancer (NSCLC), as well as pitfalls encountered with their use and areas of focus to optimize their routine clinical implementation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-839). The series “Immunotherapy in other thoracic malignancies and uncommon populations” was commissioned by the editorial office without any funding or sponsorship. JR served as the unpaid Guest Editor of the focused issue and serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep. 2019 to Sep. 2021. BB served as the unpaid Guest Editor of the focused issue. BD reports personal fees and non-financial support from Roche, non-financial support from Oxyvie, personal fees from Pfizer, non-financial support from Astra Zeneca, outside the submitted work. JR reports ADVISORY from MSD, ADVISORY from BOEHRINGER, SPEAKER from PFIZER, personal fees and TRAVEL from OSE IMMUNOTHERAPEUTICS, TRAVEL/ADVISORY from BMS, TRAVEL/ADVISORY from ASTRAZENECA, TRAVEL/ADVISORY from ROCHE, outside the submitted work. EA reports non-financial support from Travel expenses: Mundipharma, personal fees from Sanofi Genzyme, outside the submitted work. BB reports grants from Abbvie, grants from Amgen, grants from Astrazeneca, grants from BeiGene, grants from Blueprint Medicine, grants from BMS, grants from Boehringer Ingelheim, grants from Celgene, grants from Cristal Therapeutics, grants from Daiichi-Sankyo, grants from Eli Lilly, grants from GSK, grants from Ignyta, grants from IPSEN, grants from Inivata, grants from Janssen, grants from Merck KGaA, grants from MSD, grants from Nektar, grants from Onxeo, grants from OSE immunotherapeutics, grants from Pfizer, grants from Pharma Mar, grants from Roche Genentech, grants from Sanofi, grants from Servier, grants from Spectrum Phamarceuticals, grants from Takeda, grants from Tiziana Pharma, grants from Tolero Pharmaceuticals, outside the submitted work. NC reports grants from BMS Fondation, during the conduct of the study; grants from SANOFI, grants from GSK, grants and personal fees from ASTRAZENECA, grants from ROCHE, grants and other from CYTUNE PHARMA, grants from BMS Fondation, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown., Experimental Design: The percentage of CD28 - , CD57 + , KLRG1 + among CD8 + T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP + CD8 + T cells were assessed in vitro ., Results: In the ICI discovery cohort ( N = 37), SIP cut-off was 39.5%, 27% of patients were SIP + . In the ICI validation cohort ( N = 46), SIP + status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP + status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8 + T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population ( N = 83), SIP + status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort ( N = 61), 11% of patients were SIP + . SIP status did not correlate with outcomes upon PCT., Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT. See related commentary by Salas-Benito et al., p. 374 ., (©2020 American Association for Cancer Research.)

Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host's immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers.

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.