Tumor-Infiltrating Lymphocytes in Colorectal Cancer: The Fundamental Indication and Application on Immunotherapy

The clinical success of immunotherapy has revolutionized the treatment of cancer patients, bringing renewed attention to tumor-infiltrating lymphocytes (TILs) of various cancer types. Immune checkpoint blockade is effective in patients with mismatched repair defects and high microsatellite instability (dMMR-MSI-H) in metastatic colorectal cancer (CRC), leading the FDA to accelerate the approval of two programmed cell death 1 (PD-1) blocking antibodies, pembrolizumab and nivolumab, for treatment of dMMR-MSI-H cancers. In contrast, patients with proficient mismatch repair and low levels of microsatellite stability or microsatellite instability (pMMR-MSI-L/MSS) typically have low tumor-infiltrating lymphocytes and have shown unsatisfied responses to the immune checkpoint inhibitor. Different TILs environments reflect different responses to immunotherapy, highlighting the complexity of the underlying tumor-immune interaction. Profiling of TILs fundamental Indication would shed light on the mechanisms of cancer-immune evasion, thus providing opportunities for the development of novel therapeutic strategies. In this review, we summarize phenotypic diversities of TILs and their connections with prognosis in CRC and provide insights into the subsets-specific nature of TILs with different MSI status. We also discuss current clinical immunotherapy approaches based on TILs as well as promising directions for future expansion, and highlight existing clinical data supporting its use.

MuTILs: explainable, multiresolution computational scoring of Tumor-Infiltrating Lymphocytes in breast carcinomas using clinical guidelines

Tumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. We present MuTILs, a convolutional neural network architecture specifically optimized for the assessment of TILs in whole-slide image scans in accordance with clinical scoring recommendations. MuTILs is a concept bottleneck model, designed to be explainable and to encourage sensible predictions at multiple resolutions. Our computational scores match visual scores and have independent prognostic value in invasive breast cancers from the TCGA dataset.

GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models

For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.

IFN-Gamma Expression in the Tumor Microenvironment and CD8-Positive Tumor-Infiltrating Lymphocytes as Prognostic Markers in Urothelial Cancer Patients Receiving Pembrolizumab

Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8+ tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07–0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04–0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFNγ) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04–0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8+ T cells/IFNγ was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36–12.73; p = 0.0125). The combination of low CD8+ TILs and IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

Comparison of Tumor Immune Environment Between Newly Diagnosed and Recurrent Glioblastoma in Matched Patients

Purpose: Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment (TME), especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined. Methods: To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients’ GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions. Results: We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs and macrophages at initial diagnosis did not correlate with OS. TILs and macrophages were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with worse prognosis, respectively. Conclusion: Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.