Translational Medicine
Open Access

Role of Tumor-Infiltrating Lymphocytes in Predicting Immunotherapy Response

Lirael Quinholt^{* *}Correspondence: Lirael Quinholt, Department of Immunology, Ionian University, Zakynthos, Greece, Email:

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Description

Immunotherapy has revolutionized cancer treatment by harnessing the body’s immune system to recognize and eradicate tumor cells. Immune Checkpoint Inhibitors (ICIs), in particular, have demonstrated remarkable efficacy in multiple cancer types, including melanoma, non-small cell lung cancer, and bladder cancer. However, despite these advances, only a subset of patients experiences durable responses. This variability has driven intensive research to identify reliable biomarkers that can predict which patients are most likely to benefit from immunotherapy. Among these, Tumor-Infiltrating Lymphocytes (TILs) have emerged as a critical component in forecasting treatment outcomes and guiding clinical decisions [1].

TILs are immune cells-primarily T cells-that have migrated from the bloodstream into the Tumor Microenvironment (TME). Their presence indicates an active immune response against tumor cells. High levels of TILs have been associated with better prognosis in various cancers, reflecting the immune system’s capacity to recognize and mount an attack against malignant cells. Importantly, TIL density and composition can influence the efficacy of ICIs, as these therapies work by reinvigorating exhausted or suppressed T cells within the tumor [2].

The predictive value of TILs in immunotherapy is best exemplified in melanoma, one of the earliest cancers where ICIs showed success. Studies consistently demonstrate that tumors with a higher baseline infiltration of CD8⁺ cytotoxic T cells respond more favorably to anti-PD-1 and anti-CTLA-4 therapies. These cytotoxic T cells are essential effectors that directly kill tumor cells upon activation. Conversely, tumors with low TIL density often correlate with primary resistance to immunotherapy, underscoring the importance of pre-existing immunity in therapeutic response [3].

Beyond quantity, the functional status and spatial distribution of TILs are also important predictors. Not all TILs are equally effective; subsets such as exhausted T cells expressing inhibitory receptors (e.g., PD-1, TIM-3) may be less capable of tumor killing unless reinvigorated by ICIs. Additionally, regulatory T cells (Tregs) and Myeloid-Derived Suppressor Cells (MDSCs) within the TME can dampen immune responses, complicating the interpretation of total TIL counts. Recent advances in multiplex immunohistochemistry and single-cell RNA sequencing enable detailed characterization of TIL phenotypes and their spatial context, providing a more nuanced understanding of the immune landscape [4].

In breast cancer, particularly Triple-Negative Breast Cancer (TNBC), TILs have emerged as a promising biomarker for immunotherapy response. High TIL levels are associated with improved survival and better responses to ICIs in clinical trials. This has led to efforts to incorporate TIL assessment into routine pathological evaluation, standardized through guidelines from the International TILs Working Group [5].

Similarly, in Non-Small Cell Lung Cancer (NSCLC), TIL density, alongside PD-L1 expression and Tumor Mutational Burden (TMB), serves as an important biomarker triad predicting immunotherapy efficacy. The use of TILs as a predictive biomarker also extends to hematological malignancies, such as Hodgkin lymphoma, where the immune microenvironment plays a pivotal role in disease progression and response to treatment. Here, the presence of specific lymphocyte subsets correlates with better outcomes following PD-1 blockade [6].

Despite the promise of TILs as biomarkers, challenges remain in their clinical implementation. Variability in tissue sampling, processing, and assessment methodologies can affect the accuracy and reproducibility of TIL quantification. Tumor heterogeneity further complicates interpretation, as TIL density can vary significantly within different tumor regions. Moreover, the dynamic nature of the immune response suggests that a single biopsy may not fully capture the evolving tumor-immune interactions [7-8].

To overcome these hurdles, integrating TIL analysis with other biomarkers-such as PD-L1 expression, TMB, and gene expression signatures-is becoming increasingly important. Multiparametric models combining these factors have shown superior predictive performance compared to any single biomarker alone. Liquid biopsies assessing circulating immune cells and soluble factors may also complement tissue-based TIL assessment, offering less invasive and real-time monitoring options [9-10].

Conclusion

Tumor-infiltrating lymphocytes play a pivotal role in predicting response to immunotherapy across a range of cancers. Their presence and characteristics provide insight into the pre-existing immune activity within the tumor, which is essential for effective checkpoint blockade therapy. Advances in technology and standardization are enhancing the accuracy of TIL evaluation, facilitating their incorporation into clinical practice. As immunotherapy continues to evolve, leveraging TILs alongside other biomarkers promises to refine patient selection, optimize treatment strategies, and ultimately improve outcomes for cancer patients worldwide.

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