Th1–2 immune balance revisited: refining prognostic immune signatures in colorectal cancer

The prognostic relevance of the tumor immune microenvironment in colorectal cancer (CRC) is now well established. Numerous studies have demonstrated that the type, density, and spatial distribution of tumor-infiltrating immune cells critically influence clinical outcome, often outperforming conventional tumor-node-metastasis (TNM) staging in prognostic accuracy (1-5). This concept has been translated into clinical practice through the Immunoscore, which primarily quantifies cluster of differentiation (CD)3⁺ and CD8⁺ T-cell infiltration and has consistently shown robust prognostic value in stage II–III CRC (6). Nevertheless, while cytotoxic T lymphocytes have been extensively characterized, the contribution of CD4⁺ T helper (Th) cell subsets to antitumor immunity and patient prognosis remains incompletely understood.

In the context of rapidly advancing immune-profiling technologies and a growing appreciation of the functional diversity of CD4⁺ T-cell responses, the study by Ojanperä et al. (7) provides important new insights into the prognostic significance of Th1 and Th2 cells and their associated cytokine profiles in CRC. Building on prior observations that Th1-dominated immune responses are generally associated with favorable prognosis (8,9), the authors expand the field by systematically quantifying both Th1 and Th2 cell densities in large CRC cohorts and integrating these data with measurements of circulating Th1- and Th2-related cytokines. This dual-level approach, combining tissue-based immune profiling with functional immune readouts, represents a notable strength of the study.

Classically, Th1 and Th2 cells have been regarded as functionally opposing immune lineages. Th1 cells, characterized by expression of the transcription factor T-bet and secretion of cytokines such as interferon-γ (IFN-γ), tumor necrosis factor (TNF), and interleukin (IL)-2, are thought to promote antitumor immunity by enhancing cytotoxic T-cell activity and macrophage-mediated tumor cell killing (10). In contrast, Th2 cell differentiation, which requires IL-4 and is defined by the expression of GATA-binding factor 3 (GATA3) and production of cytokines including IL-4, IL-5, IL-10, and IL-13, has traditionally been linked to tumor-promoting inflammation, immune deviation, and suppression of effective antitumor responses (11,12). However, emerging evidence suggests that this binary framework may not fully capture the complexity of immune regulation within the CRC microenvironment.

Ojanperä and colleagues demonstrate that high intratumoral densities of both Th1 and Th2 cells are independently associated with improved cancer-specific survival. Importantly, these associations persist after adjustment for established clinicopathologic and molecular prognostic factors, including tumor stage, grade, mismatch repair status, and BRAF mutation. These findings corroborate earlier observations that CD4⁺ T-cell subsets contribute meaningfully to tumor control in CRC (9,13), while simultaneously challenging the notion that Th2 cell infiltration is inherently harmful.

Indeed, one of the most provocative aspects of the study is the favorable prognostic association observed for Th2 cells. Although Th2 cytokines have been implicated in colorectal tumorigenesis through epithelial IL-4 receptor signaling and immune suppression (12), experimental data have also shown that type 2 immune responses can exert antitumor effects by recruiting eosinophils, modulating macrophage polarization, and normalizing tumor vasculature (14-16). The present clinical data support this more nuanced interpretation, suggesting that Th2 cells may contribute to antitumor immunity under certain conditions rather than uniformly promoting tumor progression.

Beyond absolute immune cell densities, the authors emphasize the relevance of immune balance. The observed correlations between intratumoral Th1:Th2 cell density ratios and mesenteric serum cytokine indices suggest that local immune polarization within the tumor microenvironment is partially reflected in regional circulation. However, the relatively weak prognostic correlations of systemic cytokine levels, particularly in peripheral blood, underscore the limited significance of circulating cytokines as independent biomarkers. The comparison between local and systemic cytokine responses is an important aspect of the study, as immune responses are often highly compartmentalized. Cytokine levels measured in circulation may not accurately reflect the immune milieu at the site of inflammation, where local signals drive cellular recruitment and functional polarization. Differences between local and systemic cytokine profiles may arise from factors such as limited diffusion from tissue, rapid turnover and dilution effects in circulation. The findings align with prior studies indicating that direct assessment of the tumor immune contexture provides superior prognostic information compared with systemic inflammatory markers (1,2,5,17,18).

From a clinical standpoint, this work has several implications. First, it suggests that incorporating Th1 and Th2 cell quantification into immune-based prognostic frameworks could refine existing models such as the Immunoscore. While the Immunoscore has proven clinical value, it focuses predominantly on cytotoxic and memory T cells and does not capture the functional heterogeneity of CD4⁺ T-cell subsets (6). Expanding immune profiling to include Th cell phenotypes may therefore enhance prognostic stratification and improve biological interpretability. Second, the observation that both Th1 and Th2 infiltrates are associated with favorable outcomes, together with the finding that Th1:Th2 ratio does not appear to provide additional prognostic value, suggests that in the context of CRCs it may not be the direction of CD4⁺ T-cell polarization that is primarily determinative of clinical outcome, but rather the overall extent of CD4⁺ T-cell infiltration. From a clinical perspective, quantification of Th-cell infiltrates may therefore serve as a complementary tissue-based biomarker, particularly when integrated with established parameters such as Immunoscore-based approaches. These findings caution against therapeutic strategies aimed at broadly suppressing Th2 responses. Rather, they support immunomodulatory approaches that preserve or restore a balanced Th-cell response, potentially maximizing antitumor immunity.

The relevance of Th1–2 balance may be particularly important in the context of immunotherapy. While immune checkpoint inhibitors have revolutionized treatment for DNA mismatch repair-deficient CRC, the majority of patients with microsatellite-stable tumors derive limited benefit. A deeper understanding of the functional immune landscape, including helper T-cell polarization, may inform combination strategies designed to enhance responsiveness to immunotherapy. Whether Th1–2 composition influences sensitivity to checkpoint blockade or other immune-based treatments remains an important question for future studies.

However, several limitations of the study of Ojanperä and colleagues should be acknowledged. The retrospective design and reliance on tissue microarrays may limit the ability to fully capture intratumoral heterogeneity and introduce potential selection bias, as small tissue cores may not comprehensively reflect the spatial distribution of immune cell infiltration within the tumor microenvironment. Although the use of multiple cores and spatial sampling mitigates this limitation, it cannot entirely account for tumor heterogeneity. A key limitation of the study is the restricted immunophenotyping panel used to define Th subsets. The absence of CD4 staining prevents explicit identification of conventional CD4⁺ Th cells. Although similar minimal marker panels have been employed in other studies to infer Th1/Th2 polarization states, such approaches generally represent transcriptional signatures rather than definitive identification. Importantly, the transcription factors T-bet and GATA3 are not exclusively restricted to Th1 and Th2 cells. Complementary functional approaches, such as ex vivo assays or RNA in situ hybridization, would strengthen Th1/Th2 attribution and provide important validation of the observed phenotypes. In addition, the relatively homogeneous study population may limit generalizability to more diverse patient cohorts. Finally, while correlations between Th cell densities and cytokine profiles are informative, mechanistic studies will be required to clarify how Th2 cells contribute to tumor control in CRC.

In conclusion, the study by Ojanperä et al. provides evidence that both Th1 and Th2 cells play favorable and potentially complementary roles in CRC prognosis. By challenging the traditional view of Th2 cells as predominantly tumor-promoting, this work highlights the importance of immune balance rather than immune polarity alone. As immune profiling continues to evolve, integrating qualitative aspects of Th cell responses may prove essential for advancing prognostication and guiding future immunotherapeutic strategies in CRC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0142/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0142/coif). The authors have no conflicts of interest to declare.

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