T cells in tumor tissue are critical for both tumor immunosurveillance and elimination. CD8+ tumor infiltrating lymphocytes (TILs) can be used in pericyte therapy and are key targets for immune checkpoint inhibitors. CD8+ TILs are associated with survival in many tumor types. By learning TIL formation and differentiation, a more accurate understanding of the response status of T cells in the tumor microenvironment can be obtained, providing a possible strategy for treating patients who are unresponsive to ICB (immune checkpoint blockade). Despite the fact that extensive research has examined the heterogeneity of TILs, a more thorough and in-depth approach to TIL classification and status resolution, as well as the integration of TIL status with patient responsiveness, is required.
Niroshana Anandasabapathy's team from Weill Cornell Medical College's has published an article in Cancer Cell titled "An activation to memory differentiation trajectory of tumor-infiltrating lymphocytes informs metastatic melanoma outcomes", highlighting the characteristics of persistent resident memory TIL cells linked with ICB responsiveness and providing a comprehensive investigation of TILs in malignancies.
Using publicly accessible datasets, the authors first analyzed naïve CD8+ T cells, memory effector TEM, central memory TCM, and resident memory TRM isolated from skin, lung, intestine, and brain following multiple viral infections. The authors verified that deletion of Runx3 resulted in the absence of activation and immune checkpoint expression, while expression of Runx3 promoted the expression of both types of molecules. Testing this group of TRM, the authors verified that they simultaneously express tissue-resident related markers.
They next began to analyze TILs by performing a single-cell transcriptome analysis of 1500 CD3+ TILs isolated from 13 patients with metastatic melanoma. The result revealed that approximately two-thirds of the TILs had high TRM scores and that TILs with high TRM profiled highly expressed immune checkpoints and immune activation markers. These results suggest that resident TILs can express both immune checkpoints and immune activation-related molecules.
The authors further analyzed the status of individual TILs and found that individual TIL can have more than one T cell state characteristic, including activation state, depletion state, and resident memory state. The authors also analyzed the differences between TILs in ICB unresponsive melanoma and responsive melanoma. Analysis of TIL modeling revealed that ICB unresponsive melanoma had a high proportion of early activating TILs, whereas reactive melanoma had an expanded cluster of resident memory T cells. Increased frequency of early activation-like T cells was associated with a lack of responsiveness, and increased persistent resident memory-like T cells were associated with patients having responsiveness to ICB.
The team also performed a transcriptome comparison using viral or vaccine-driven T cell states with human melanoma TILs, which revealed a greater overlap between viral and vaccine-driven T cell states and melanoma TIL states, rather than incompetent or depleted T cell states.
It was discovered that TIL features in different tumor types were associated with early activation of T cell status-related exhaustion. The process of TIL growth in different cancers is similar to that of melanoma-associated TIL cell cluster development, and this process has conserved features. Furthermore, this mechanism is linked to the development of memory T cells or virally activated T cells.
Finally, the researchers analyzed that persistent TIL memory-like cell characteristics correlated with survival prognosis in melanoma patients and allowed for stratified patient management. Persistent and memory resident TILs correlated with DC and IFNg responsiveness and predicted patients with better survival and responsiveness to ICB. In contrast, early activated TIL characteristics do not predict patient survival prognosis.
This study used a systems biology approach with single-cell transcriptomic data to uncover the link between CD8+ TIL differentiation and patient survival as well as ICB treatment responsiveness.
