The ability of human cancers to avoid destruction by the immune system has baffled many immunologists and cancer researchers alike. Unlike the autoimmune disease area of research where the role played by patient genetics in mediating immune attack is well acknowledged and extensively studied, in the field of cancer research, the contribution of patient-specific germline variants in mediating immune escape in the tumor environment has remained vastly underappreciated.
I am a strong proponent of the concept that germline genome-encoded variants play a deterministic role in cancer progression as well as response to systemic therapies (Read my 2018 article on Technology Networks). This is an extremely challenging concept to investigate in the absence of a genetic variant knock-in mice. We have developed a new methodology to circumvent the need for a SNV knock-in transgenic mice.However, it is clear that in pursuing this idea, new opportunities will open up for understanding the individual-specific aspect of cancer biology and also to uncover biomarkers for patient stratification. Hopefully, the new knowledge generated will also help reduce unnecessary exposure to therapy-induced toxicities and poor prognosis - an aspect that is very important for individualized medicine.
Human tumors are heterogeneous mixture of diverse cell types comprising of somatically altered cancer cells, infiltrating immune cells, stromal cells, fibroblasts and other cell types some of which may even exhibit plasticity. Of all these diverse assemblages, the immune component of human tumors has gained much attention recently due to its very convining predictive value for the therapy response in many cancer types. The immune contexture comprising of multiple immune cell types, is different in different patient individuals. However, FOXP3-expressing regulatory T cells (Tregs) and cytotoxic CD8 T cell infiltration appear to be crucial determinants of survival prospects in end-stage cancer patients (Bruni, D et al, Nat Rev Cancer 20, 662–680 (2020) ).
The real challenge is to figure out why some individuals have tumors with extremely low CD8/Tregs ratio. Many ideas are currently put forward by several investigators. Almost all of them are fixated on the engagement of T cell receptor (TCR) complex because the functional properties of CD8 and Treg are governed by TCR signalling.
The functional properties of all kinds of T cells are controlled by two kinds of membrane proteins, namely,
- T cell receptor complex (TCR) and,
- Co-signalling receptors (CSRs)
These two kinds of membrane proteins on T cell membranes function by generating tyrosine phosphorylation reaction on the inner side of cell membrane when bound to the ligands. The ligands are found on the cell membranes of antigen-presenting cells (APCS) or cancer cells. Ligand-receptor interaction is triggers a cascade of protein tyrosine phosphorylation events ultimately reaching the nucleus where a transcription program is generated that dictates the typical antigen-specific cell mediated immune response viz,
- Proliferation,
- Migration,
- Cytokine production and,
- Cytotoxicity
My contention is that in humans, the engagements of TCR and CSRs generate varied signalling propensities due to one or more germline variants at the juxtamembrane segments which are unique to patients. In other words, rare patient-specific genetic variants occurring in the membrane-proximal signalling apparatus dictates the quality of tumor antigen-specific cell mediated immune response. This is based on the idea that human genome harbors such germline variants that impact proximal phosphotyrosine signalling pathways.
The first evidence for such a variant was uncovered by the discovery of rs351855-G/A by Axel Ullrich and the subsequent work that demonstrated an rs351855-A allele-specific molecular function of elevating tyrosine phosphorylation of STAT3 (Ulaganathan VK et al, Nature 528, 570–574, (2015)).
Today, we have the information that the human genome harbors about 50 rare germline variants that has the capacity to elevate tyrosine phosphorylation of STAT3 in immune cells including Tregs, CD8 T cells, CD4 T cells, B cells, NK cells, Dendritic Cells and Macrophages (see this TraPS-VarI Weblog for tabulated expression profiles). This information is poised to change how we view the regulation of the levels of tyrosine phosphorylated STAT3 in immune cells derived from different human individuals.
STAT3 is a very important transcription factor which is ubiquitously expressed and exhibits distinct functions in different cell types. Every immune cell types contain STAT3 proteins in the cytoplasm. However, the entry of STAT3 into the nucleus is necessary to drive a STAT3-dependent transcription program, and this is often very cell type-specific. There are many cell surface receptors that can recruit cytoplasmic STAT3 to inner membrane to activate this transcription factor by tyrosine phosphorylation. In other words, translocation of STAT3 to the nucleus is governed by the membrane-proximal signalling events that modifies cytoplasmic STAT3 by phosphorylating the tyrosine resulting in its activation and subsequent translocation to the nucleus.
Activated STAT3 in professional antigen presenting cells (APCs) such as macrophages and dendritic cells inhibits the antigen presenting capacities, thereby suppress T cell mediated antigen-specific immune response. On the other hand, activated STAT3 in CD4 and CD8 T cells enhance the antigen-specific T cell response by enhancing proliferation, cytokine production and migration. However, enhanced functional capacities mediated by activated STAT3 in Tregs does the opposite as it mediates the suppression of effector CD4 and CD8 T cells. Thus, tyrosine phosphorylation of STAT3 (STAT3-pY705) appears to be the "rheostat" of antigen-specific cell mediated immune response. Depending on which side the knob is moved in terms of highest levels of STAT3-pY705 in either APCs or effector T cells or Tregs, the output is tuned towards either aggressive, optimal, sub-optimal or subdued antigen-specific T cell response.
So how does this new knowledge about patient-specific germline variant that elevate levels of STAT3-Y705 help us understand the individuality of CD8/Treg ratio in the tumor microenvironment?
If a patient harbors one or multiple germline variants that elevates STAT3-pY705 in APCs or Tregs, the anticipated outcome is either sub-optimal or subdued tumor-antigen-specific T cell response.
And if a cancer patient harbors one or multiple germline variants that elevates STAT3-Y705 in CD4 or CD8 T cells, the likely outcome is either optimal or aggressive tumor antigen-specific T cell response.
These are the ideas that we are currently investigating in our research project in collaboration with your clinical partners.
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