MFSD2A potentiates gastric cancer response to anti‐PD‐1 immunotherapy by reprogramming the tumor microenvironment to activate T cell response

Abstract

BackgroundThe efficacy of anti‐programmed cell death protein 1 (PD‐1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti‐PD‐1 therapeutic response in advanced GC (AGC).MethodsThe transcriptome of AGC tissues from patients with different clinical responses to anti‐PD‐1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real‐time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti‐PD‐1 response by MFSD2A was studied in tumor‐bearing mice. Cytometry by Time‐of‐Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.ResultsHigher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti‐PD‐1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti‐PD‐1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8+ T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor β1 (TGFβ1) release from GC cells by suppressing cyclooxygenase 2 (COX2)‐prostaglandin synthesis, which consequently reprogrammed TME to promote anti‐tumor T cell activation.ConclusionsMFSD2A potentially serves as a predictive biomarker for anti‐PD‐1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti‐PD‐1 immunotherapy by reprogramming the TME to promote T cells activation.

Exploring the immune escape mechanisms in gastric cancer patients based on the deep AI algorithms and single‐cell sequencing analysis

“… 19 , 20 However, there is significant interindividual variability in the response and tolerability of gastric cancer patients to immunotherapy, with some benefiting significantly while others fail to achieve the desired therapeutic effects. 21 , 22 Consequently, understanding the immune molecular characteristics and immune escape mechanisms of gastric cancer patients is of paramount importance for individualized design and prediction of immunotherapy efficacy.…”

“…19,20 However, there is significant interindividual variability in the response and tolerability of gastric cancer patients to immunotherapy, with some benefiting significantly while others fail to achieve the desired therapeutic effects. 21,22 Consequently, understanding the immune tumour microenvironment, thereby affecting the development and progression of gastric adenocarcinoma. 34 The polarization state of M2 macrophages promotes tumour angiogenesis and progression in the tumour microenvironment by releasing cytokines, such as pro-angiogenic factors and growth factors.…”

Dietary long‐chain fatty acid metabolism boosts antitumor immune response

“…On the other hand, immunometabolism also modulates tumor‐associated immune cell function and immunotherapy efficacy. For instance, higher expression of major facilitator superfamily domain containing 2A (MFSD2A) in gastric cancer cells inhibits transforming growth factor beta 1 (TGF‐β1) production by suppressing cyclooxygenase 2 (COX2)‐prostaglandin synthesis, thus promoting antitumor immunity via reprogramming TME [ 3 ].…”

Predictive Factors of Immunotherapy in Gastric Cancer: A 2024 Update

“…MFSD2A may function as a prognostic biomarker for the response to anti-PD-1 immunotherapy in AGC patients. A potential therapeutic target for improving the efficiency of anti-PD-1 immunotherapy appears to be MFSD2A, which reprograms the tumor microenvironment (TME) to support T-cell activation [ 16 ]. Lower CD4+ T, CD4+ (naive) Tn, CD4+ Tm, CD4+ (central memory) Tcm, and CD4+ (effector memory) Tem cell frequencies expressing PD-1 were found to be independent risk factors for PFS and OS in AGC patients treated with combined immunotherapy and chemotherapy according to univariate and multivariate Cox regression analyses.…”

“…disulfidptosis-related gene prognostic risk model [4] -M2 macrophages were strongly correlated with a high PANscore [5] predictive signature AC129926.1, AC023511.1, AP002954.1, LINC01537, and TMEM7 based on CRLs [6] -ARLSig has strong predictive value for the survival of GC patients [7] -PRS was created using the TCGA, GSE15459, GSE26253, GSE62254, and GSE84437 datasets [8] -PI3K pathway linked to PD-L1 positivity is linked to increased immunotherapy efficacy [9] potentially valid serum predictive markers for identifying individuals who might profit from PD-1 inhibitors paired with chemotherapy include IL-6, IL-2, IL-17A, and NLR [10] -PD-L1+CD68+ macrophages may be a viable prognostic indicator in primary GC patients [11] -ITGB1 may be an effective prognostic biomarker and a useful predictor of outcome for GC patients receiving anti-PD-1 medication [12] a reduced tumor mass, absence or small number of lymph node metastases, and a large combined positive score; neoadjuvant chemotherapy plus PD-1 antibodies for the prediction of pCR in AGC patients undergoing neoadjuvant chemotherapy combined with PD-1 antibody immunotherapy [13] memory PD-1+CD8+ T cells and the ratio of PD-1+CD8+ T cells to PD-1+CD4+ T cells may be useful for identifying individuals who would benefit from immunotherapy among AGC patients [14] the CD4+/CD8+ ratio may be a potential predictive indicator for patients under PD-1 inhibitor-based combination therapy for advanced gastric and esophageal cancer, and it can independently predict dermatological damage [15] -MFSD2A may function as a prognostic biomarker for the response to anti-PD-1 immunotherapy in AGC patients [16] the peripheral CD4+ T-cell subset has shown significant predictive value for therapeutic response and longer survival in AGC patients [17] patients with GC receiving combination immunotherapy are predicted to respond better when HSPA4 is upregulated [18] the combination of Tregs, Ki-67, and age (65 years or older) can more accurately predict the likelihood of unfavorable responses [19] the incidence of irAEs could serve as a stand-in marker for ICIs [20] utilizing biomarkers based on the numbers of various lymphocyte subpopulations, it is possible to predict the clinical prognosis and efficacy of immunotherapy in patients with AGC [21] a negative correlation between CRABP2 and the immune checkpoint markers PD-1, PD-L1, and CTLA-4 was observed [22] Table 2. Major developments in genetic predictive factors research.…”