Deciphering the prognostic weight of tumour-cell CTLA-4 in gastric carcinoma: The need for molecular stratification

Sir,

I read with great interest the article by Kottarathil et al ¹ published in the December 2025 issue of the Indian Journal of Medical Research exploring the expression of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in gastric carcinoma and its correlation with histopathological parameters. The authors provide a timely contribution to our understanding of the immune landscape in gastric cancer, particularly by shifting the focus toward CTLA-4 expression on tumour cells themselves, rather than exclusively on tumour-infiltrating lymphocytes (TILs). Given the expanding role of immune checkpoint inhibitors (ICIs) in the management of gastrointestinal malignancies, elucidating novel biomarkers is of paramount clinical importance.

The finding that high tumour-cell CTLA-4 expression is significantly associated with advanced T-stage (pT3 and pT4) and nodal metastasis is particularly noteworthy. It suggests that CTLA-4 may not only serve as a target for therapy but also as a surrogate marker for tumour invasiveness. However, while these observations are compelling, a few constructive reflections are offered here to further refine the interpretation of these data in the context of current precision oncology.

First, the heterogeneity of gastric adenocarcinoma is now well-recognized, largely defined by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group classifications.² It is established that molecular subtypes—specifically, microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive tumours—exhibit distinct immune microenvironments and significantly higher responses to ICI therapy.³ In this study, the absence of data regarding MSI or EBV status makes it difficult to discern whether the observed CTLA-4 expression is an independent driver of aggression or a reflection of a specific underlying molecular subtype. Integrating these molecular characteristics would greatly enhance the generalizability of the results to a global patient population.

Second, although the authors identified a statistically significant association between CTLA-4 and tumour stage, the modest sample size (n=50) inevitably limits the statistical power to perform multivariate Cox regression analysis. Gastric cancer prognosis is influenced by a complex interplay of factors, including lifestyle variables and prior treatments, which were included ‘irrespective of adjuvant therapy status’ in this cohort. Without adjusting for these potential confounders, ascribing an independent prognostic value to CTLA-4 expression remains a challenge.⁴

Finally, the biological role of tumour-cell intrinsic CTLA-4 expression remains an area of active debate. Unlike its well-characterized inhibitory role on T-cells, tumour-cell CTLA-4 may involve non-canonical signalling pathways, such as the upregulation of the EGFR pathway or PD-L1 modulation, as hinted at in other malignancies.⁵ I believe that future studies incorporating functional assays or larger-scale transcriptomic data would be invaluable in confirming whether tumour-cell CTLA-4 is a ‘passive’ marker of high-grade disease or an ‘active’ participant in immune evasion.

In conclusion, I commend the authors for their insightful work. Their findings provide a solid foundation for future research. I would be eager to see if future analyses, perhaps in a larger multicentre cohort, could validate these findings while adjusting for the molecular subtypes that currently dictate our clinical decision-making.

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