RESIDENT LYMPHOCYTES KEEP A LOOKOUT FOR NASCENT CANCER CELLS

 

By Sophie Balmer, PhD

One of the first questions that comes to my mind when discussing the emergence of cancer cells is how my immune system recognizes that my own cells have been transformed? This process is commonly termed cancer immunosurveillance. In the prevalent model, the adaptive immune system composed of lymphocytes circulating in the blood stream plays the main function. However, recent findings describe specific immune cells already present within the tissue, a.k.a. tissue-resident lymphocytes, and how they trigger the first immune response against cancer cells, allowing a much faster reaction in an attempt to eradicate transformed cells.

 

The cancer immunosurveillance concept hypothesizes that sentinel thymus-derived immune cells constantly survey tissues for the presence of nascent transformed cells. Cancer immunosurveillance was first suggested in the early 1900’s by Dr. Erlich but it took another fifty years for Dr. Thomas and Dr. Burnet to revisit this model and speculate about the presence of transformed cells induced inflammation and antigen-specific lymphocyte responses. Additionally, Dr. Prehn and Dr. Main estimated that chemically-induced tumor triggered the synthesis of antigen at the surface of cancerous cells that could be recognized by the immune system. Countless studies arose from these hypotheses and either validated or disproved these models. The latest attempt was published a little over a month ago, in a paper by Dr. Dadi and colleagues, describing a new mechanism for the immune system to respond to nascent cancer lesions by activating specific resident lymphocytes.

 

In this study, the authors used a genetically-induced tumor model (the MMTV-PyMT spontaneous mammary cancer mouse model) to analyze the in vivo response of the immune system to nascent transformed cells. Most studies have been performed using chemically-induced tumors or tumor transplantation into a healthy host but these do not account for the initial environment of the nascent tumor. The spontaneous model the authors use rapidly exhibits developing cancer lesion (in 8-week old mice), allowing the analysis of cellular populations present near transformed cells.

 

To analyze which immune cell types are present near cancer lesions, the authors performed several analyses. First, they measure the levels of granzyme B, a serine protease found in granules synthesized by cytotoxic lymphocytes to generate apoptosis of targeted cells, and show that PyMT mice have elevated levels of granzyme B when compared to wild-type mouse. Moreover, similar analysis of PyMT secondary lymphoid organs show that this response was restricted to the transformed tissue.

During the first steps of immune responses, conventional natural killer (cNK) cells as well as innate lymphoid cells (ILC) are found in tumor microenvironments. In this model however, sorting of cells located in the vicinity of the lesion identified unconventional populations of immune cells, derived from innate, TCRab and TCRgd lineages. Indeed, their RNA-seq profiling reveal a specific gene signature characterized by high expression of the NK receptor NK1.1 but also the integrins CD49a and CD103. As these newly identified cells share part of their transcriptome with type 1 ILCs, the authors named them type 1-like ILCs (ILC1ls) and type 1 innate-like T cells (ILTC1s). In addition, transcripts encoding several immune effectors as well as apoptosis-inducing factors are upregulated in these cells, likely indicating that they trigger several pathways to eliminate transformed cells.

The authors also suggest that cNK cells are not required for immunosurveillance in this model and the unconventional lymphocytes described in this paper are regulated by the interleukine-15 (IL-15) in a dose-dependent way. Mice overexpressing IL-15 exhibit higher proliferation of these resident lymphocytes and tumor regression. Secretion of IL-15 in the tumor microenvironment might therefore promote cancer immunosurveillance.

 

In contradiction with the conventional view that recirculating populations of immune cells survey tissues for cellular transformation, ILC1ls and ILTC1s are tissue-resident lymphocytes. Their gene signature indicates that transcripts encoding motility-related genes are downregulated in these cells. Moreover, parabiosis experiments, during which two congenically marked mice are surgically united and share their blood stream, are performed to determine whether they are resident or circulating cells. The amounts of non-host ILC1s and ILTC1s are much reduced when compared to other recirculating immune cell type demonstrating that these cells are tissue-resident lymphocytes. Single-cell killing assays also determine that ILC1ls and ILTC1s are highly efficient at inducing apoptosis of tumor cells, which is more likely dependent on the lytic granules pathway.

 

Although the cancer immunosurveillance concept has been around for decades, it is still highly debated. Overall, these results shed light on this confusing field and bring up several questions. The signals recognized by this immune response are still unknown. Although the authors suggest that IL-15 might regulate the proliferation and/or activation of these cells, the source of IL-15 remains to be found. In addition, these cells might promote cancer immunosurveillance but are not sufficient to eradicate tumor cells and determining the cascade of signals induced by these resident lymphocytes will be required to ascertain their role. Establishing the limit of their efficiency as well as the mechanisms activated by transformed cell to escape their surveillance will also be crucial. Finally, one of the most important question to consider is how one could manipulate the activity of tissue-resident lymphocytes in cancer immunotherapy.