Integrating Circulating Biomarkers in the Immune Checkpoint Inhibitor Treatment in Lung Cancer

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

Overcoming resistance to αPD-1 of MMR-deficient tumors with high tumor-induced neutrophils levels by combination of αCTLA-4 and αPD-1 blockers

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

Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

International audienceGut 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