Unraveling the Role of Immune Cells in Melanoma Immunotherapy

A patch of malignant melanoma approx. 2cm. (Image Credit: National Cancer Institute)

Introduction

Melanoma, a serious form of skin cancer, has become a focal point in cancer research due to its aggressiveness and the challenges it presents in treatment. However, with the advent of immunotherapy, particularly checkpoint blockade immunotherapy (CBI), there has been significant progress in treating melanoma. This blog will explore the recent findings from a study on how specific immune cells, particularly subsets of CD8 T cells and dendritic cells (cDC1), contribute to the effectiveness of immunotherapy in melanoma.

Understanding the Immune Landscape in Melanoma Immunotherapy

The immune system's role in fighting cancer is complex and involves various cells that work together to detect and destroy cancer cells. CD8 T cells, often referred to as "killer" T cells, are crucial in this fight. They are responsible for directly attacking and eliminating cancer cells. However, the effectiveness of these cells can vary depending on their environment and the signals they receive from other cells, such as dendritic cells.

Checkpoint Blockade Immunotherapy (CBI)

Checkpoint blockade immunotherapy is a type of treatment that helps the immune system recognize and attack cancer cells more effectively. Normally, checkpoint proteins on immune cells act as brakes, preventing them from attacking normal cells. However, cancer cells can exploit these checkpoints to avoid being attacked by the immune system. CBI drugs, such as anti-PD1, work by blocking these checkpoints, effectively releasing the brakes and allowing the immune system to target cancer cells.

Key Findings from the Study

The study highlights the importance of two subsets of tissue-resident memory (TRM) CD8 T cells: TCF1-positive (TCF1+) and TCF1-negative (TCF1−) cells, along with cDC1 dendritic cells, in controlling melanoma and responding to immunotherapy.

CD103+CD8 T cells associate with disease control. Diagram of study design.

TCF1+ and TCF1− TRM CD8 T Cells:

• TCF1+ TRM Cells: These cells are considered progenitor-like, meaning they are in an early stage of development but can proliferate and become more effective at killing cancer cells. They express markers such as IFN-γ and Ki67, indicating their ability to fight cancer and multiply.

• TCF1− TRM Cells: These cells are more differentiated and have a higher expression of cytotoxic molecules, which are proteins that help them kill cancer cells directly. However, they also show signs of exhaustion, a state where immune cells become less effective due to constant stimulation by cancer cells.

CD103+ CD8 T cells are bona fide TRM cells and both TCF1− and TCF1+ subsets are protective. (A) Representative micrographs of immunofluorescence (IF) staining for TCF1 (green), CD103 (yellow), CD8 (red), and nuclei (blue). Dotted white squares show the area selected for digital zoom in the right column. White squares point out to an example of TCF1+CD103+ CD8 T cells, and yellow squares point out to TCF1− CD103+CD8 T cell.

cDC1 Dendritic Cells:

• cDC1 cells are specialized in presenting antigens, which are pieces of cancer cells, to CD8 T cells. This presentation is crucial for activating CD8 T cells and guiding them to target and destroy cancer cells. The study found a close spatial relationship between cDC1 cells and TRM cells in the tumor environment, suggesting that these cells work together to enhance the immune response against melanoma.

There is a high correlation between the enrichment of TRM CD8 T cells and cDC1, which is associated with patient survival. (A) Kaplan-Meier survival curves for TRM CD8 T cells (top) and dendritic cell type 1 cDC1 (bottom). Curves show a comparison over the course of 180 months between high versus low enrichment samples.

TCF1+ and TCF1− TRM CD8 T cells exhibit differential functional features.

The Shift in TRM Cells During Disease Progression

In patients with metastatic melanoma (where the cancer has spread to other parts of the body), the study observed a shift in the expression of markers in TRM cells. TCF1− TRM cells in these patients showed increased exhaustion markers, which could explain why these patients have a poorer response to immunotherapy. Despite this, both TCF1+ and TCF1− TRM cells are essential for controlling melanoma, highlighting the need for strategies that can rejuvenate these exhausted cells.

Spectral flow cytometry validates the protection of TCF1+ TRM CD8 T cells and the shift to a more exhausted TCF1− cell in metastatic patients.

Implications for Immunotherapy

The presence of TCF1+ TRM cells and cDC1 dendritic cells is associated with better responses to immunotherapy. This suggests that assessing the levels of these cells in melanoma patients before starting treatment could help predict how well a patient will respond to immunotherapy. Moreover, therapies that can boost the function of TCF1− TRM cells or prevent their exhaustion could improve outcomes for patients with advanced melanoma.

Conclusion

This study provides valuable insights into the immune mechanisms that contribute to the success of immunotherapy in melanoma. By understanding the roles of different TRM CD8 T cell subsets and cDC1 dendritic cells, researchers and clinicians can better tailor treatments to individual patients, potentially improving survival rates and quality of life for those battling this aggressive cancer.

Immunotherapy has revolutionized the treatment landscape for melanoma, and ongoing research continues to uncover the intricate dance between the immune system and cancer cells. As we deepen our understanding of these processes, the hope is to develop even more effective treatments that can outsmart cancer at every turn.

Source(s):

De León-Rodríguez SG, Aguilar-Flores C, Gajón JA, et al

TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response

Journal for ImmunoTherapy of Cancer 2024;12:e008739. doi: 10.1136/jitc-2023-008739