The Folate Pathway Inhibitor Pemetrexed Pleiotropically Enhances Effects of Cancer Immunotherapy

Abstract

Purpose: Combination strategies leveraging chemotherapeutic agents and immunotherapy have held the promise as a method to improve benefit for patients with cancer. However, most chemotherapies have detrimental effects on immune homeostasis and differ in their ability to induce immunogenic cell death (ICD). The approval of pemetrexed and carboplatin with anti-PD-1 (pembrolizumab) for treatment of non-small cell lung cancer represents the first approved chemotherapy and immunotherapy combination. Although the clinical data suggest a positive interaction between pemetrexed-based chemotherapy and immunotherapy, the underlying mechanism remains unknown.Experimental Design: Mouse tumor models (MC38, Colon26) and high-content biomarker studies (flow cytometry, Quantigene Plex, and nCounter gene expression analysis) were deployed to obtain insights into the mechanistic rationale behind the efficacy observed with pemetrexed/anti-PD-L1 combination. ICD in tumor cell lines was assessed by calreticulin and HMGB-1 immunoassays, and metabolic function of primary T cells was evaluated by Seahorse analysis.Results: Pemetrexed treatment alone increased T-cell activation in mouse tumors in vivo, robustly induced ICD in mouse tumor cells and exerted T-cell-intrinsic effects exemplified by augmented mitochondrial function and enhanced T-cell activation in vitro. Increased antitumor efficacy and pronounced inflamed/immune activation were observed when pemetrexed was combined with anti-PD-L1.Conclusions: Pemetrexed augments systemic intratumor immune responses through tumor intrinsic mechanisms including immunogenic cell death, T-cell-intrinsic mechanisms enhancing mitochondrial biogenesis leading to increased T-cell infiltration/activation along with modulation of innate immune pathways, which are significantly enhanced in combination with PD-1 pathway blockade.See related commentary by Buque et al., p. 6890

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

“…Interestingly, a recent study described enhanced immune control of tumors with combination TS inhibitor (pemetrexed) and anti-PD-L1 blockade, with clear evidence of heightened T cell priming, increased intratumoral leukocytes, and a greater T cell inflamed phenotype (Schaer et al, 2019). Our results are consistent with their observations of tumor immunogenic cell death, and higher levels of MHC class I on transformed cells may provide greater sources of tumor specific antigens.…”

Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer

“…These results are in agreement with recent findings showing that pemetrexed treatment in murine syngeneic colon tumor models (MC38 and Colon 26) activated T cells, inducing an inflamed phenotype, and that the addiction of an anti PD-L1 antibody improved the anti-tumor properties of the anti-folate compound [27].…”

Alectinib-induced Immune Hemolytic Anemia in a Patient with Lung Adenocarcinoma

“…In the present patient, first-line pemetrexed therapy may have contributed to the onset of alectinib-induced IHA. Cases of rheumatoid arthritis induced by pemetrexed therapy have been reported (11), and recent investigations have demonstrated that pemetrexed promotes lymphocyte activation (12). For this reason, first-line pemetrexed therapy probably induced autoantibody production and caused alectinibinduced IHA despite pemetrexed discontinuation.…”