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Patient-specific genetic mutations dictate T cell-augmenting immunotherapy outcomes

Image credit: Image created by Vijay_Ulaganathan (https://traps-vari.org/weblog/K/)

ViJay K. U. Nathan; B.Pharm, M.Tech (BioEngg), PhD
ViJay K. U. Nathan; B.Pharm, M.Tech (BioEngg), PhD Feb 21, 2021
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Unsolved Problems of Cancer Immunotherapy
When diagnosed with advanced, malignant melanoma – a type of skin cancer, surgery alone isn't enough to control it. T cell augmenting immunotherapy has recently become an important treatment option to control and prolong lives of terminal cancer patients. Immunotherapy enhances one’s own immune system's ability to repress melanoma that has spread from the original tumor to other parts of your body. Sadly, not all patients respond well to immunotherapies. Which patient will respond well to the treatment is hard to predict and is currently one of the biggest unsolved challenge in the field of immuno-oncology.

The General Idea
Unlike laboratory mice which are inbred and genetically similar, human individuals in the general population are out-bred and genetically diverse. Even though genetic diversity causes 20–40% of the variation between the immune systems of individuals, which genetic variants are linked to differences in tumor-fighting immune responses is not clarified in the field of cancer research. Elucidating the mechanistic basis of germline mutations that underlie the individual-individual variability in anti-tumour T-cell responses will improve patient response rates by facilitating individualized patient-specific immunotherapy treatments.

Why I am proposing this Idea?
In my previous study, I showed for the first time that cancer patient-specific germline mutation that expose phosphotyrosine-based SH2 domain-binding (p)YxxQ motif accelerate tumour progression by recruiting STAT3 to inner membranes, thereby enhancing tyrosine phosphorylation of STAT3 (Ulaganathan et al Nature 2015). Additionally, I showed that such STAT3 enhancing single nucleotide polymorphic mutations (SeSNPs) directly control the functional properties of T cells in the tumour lesions in a manner that is independent of tumour types (Kogan et al JCI 2018). Recently, an in-depth analysis of large whole genome sequencing and genotyping datasets from multiple cancer cohorts revealed that in addition to SeSNPs, mutations that either create or delete immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activation motifs (ITAMs) are also prevalent in the germline genomes of cancer patients (Ulaganathan VK Sci. Rep 2020).

These recent research provides valid basis to propose the idea that patient-specific genetic mutations (heritable/running in families) is likely responsible for differences in T cell augmenting immunotherapy outcomes.

Specific Problem I attempt to solve with this Idea
The co-receptors CTLA-4 and PD-1 immune checkpoints are negative regulators of T-cell immune
function. Inhibition of these targets resulting in increased activation of the immune system, has led to a
radically new way for treating malignant melanoma. The research leading to this kind of therapy was awarded Nobel Prize in Medicine in 2018. However, only a minority of patients really enjoy the long-term benefit from ICB therapies. About 50-80% of patients do not benefit due to non-responsiveness to therapy or therapy-induced autoimmune toxicities.
I am putting forward this idea that polymorphic human genetic variations in programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is associated with poor prognosis and adverse effects of immune checkpoint blockade (ICB) therapy.

What is the specific Idea?
I postulate the hypothesis that certain single nucleotide polymorphic (SNP) genetic variation in the coding sequence of CTLA4 and PD-1 is associated with anti-tumour CD8 T cell responses in patients and therefore impact the therapeutic outcomes of ICB mAb therapy either alone, in sequence or in combined form. To test this hypothesis, my research group will first begin gathering clinically relevant information:-

(i) Are SNPs in PD-1 and CTLA4 associated with malignancy in melanoma patients?
(ii) Is there a correlation between genetic mutations in PD-1 and CTLA-4 with the activation state of
circulating CD8 T cells?
(iii) Is there a correlation between genetic mutations in PD-1 and CTLA-4 with the therapeutic and
survival outcomes of patients receiving ICB therapy?

Brainstorming Tips !
I am looking for anecdotal stories linked to this idea. For instance, immunotherapy not working or similar adverse effects/therapy-induced toxicities found in patients from certain family or ethnic backgrounds.

Any counter ideas and arguments against or in favour of this idea are welcome.

Relevant Publications
1: *Ulaganathan VK. TraPS-VarI: Identifying genotype-specific immunoreceptor tyrosine based
sequence motifs. Scientific Reports. 10, Article number: 8453 (2020)
doi: https://doi.org/10.1038/s41598-020-65146-2
2: Kogan D, Grabner A, Yanucil C, Faul C, *Ulaganathan VK. STAT3-enhancing germline
mutations contribute to tumor-extrinsic immune evasion. J Clin Invest. 2018 Feb 13.
doi: https://doi.org/10.1172/JCI96708
3: *Ulaganathan VK, Sperl B, Rapp UR, *Ullrich A. Germline variant FGFR4 p.G388R exposes a
membrane-proximal STAT3 binding site. Nature. 2015 Dec 24; 528 (7583):570-4.
doi: https://doi.org/10.1038/nature16449
*corresponding author

Media Releases
1: Tumor-extrinsic Immune Evasion in the Tumor Microenvironment (2018, May 17). Technology
Networks: Exploring the Science that Matters to You
2: Gene variation promotes uncontrolled cell division (2016, Dec 16). Max-Planck-Gesselschaft


Creative contributions

(ii) Genetic mutations in PD-1 and CTLA-4 correlate with the activation state of circulating CD8 T cells

Shubhankar Kulkarni
Shubhankar Kulkarni Feb 25, 2021
I think the answer to your question (ii) depends on the SNP. Here is a review that mentions the sites and the specific mutations that might inhibit the function of PD-1, which will result in the promotion of T-cell proliferation and activation. In particular, the section "A single mutation renders PD-1 non-functional" from the reference is useful. Therefore, I would say that a correlation of genetic mutations in PD-1 and CTLA-4 with the activation state of circulating CD8 T cells is not impossible.

Other references that might be useful:

[1]Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-125. doi:10.1111/j.1600-065X.2009.00767.x

[2]Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111-122. doi:10.1016/j.immuni.2007.05.016

[3]Sharpe, A., Freeman, G. The B7–CD28 superfamily. Nat Rev Immunol 2, 116–126 (2002). https://doi.org/10.1038/nri727

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General comments

Shubhankar Kulkarni
Shubhankar Kulkarni3 years ago
Hi ViJay K. U. Nathan; B.Pharm, M.Tech (BioEngg), PhD ! Welcome 😄 . I admire your extensive research.

Here are a few questions and comments from my side:
1. Are SNPs in PD-1 and CTLA4 associated with malignancies in all subtypes of melanoma? - If we don't know the answer to this question, it might be a good option to start your research by answering this. It will help you eliminate those subtypes that are not affected by SNPs in PD-1 and CTLA4. You know that there also exist a large number of differences (in terms of the mutations) across the subtypes. This is one of the reasons we are moving towards personalized therapy for cancer patients. It will, therefore, be helpful if the affected subtypes are identified and studied separately.
2. You mentioned that only certain SNPs in PD-1 and CTLA4 are associated with anti-tumour CD8 T cell responses. Do we know which are these specific SNPs? If not, it makes sense to identify them as well. A reduced list of SNPs will be easier to perform a literature search (to answer questions (ii) and (iii) from your list).
Please leave the feedback on this idea
ViJay K. U. Nathan; B.Pharm, M.Tech (BioEngg), PhD
ViJay K. U. Nathan; B.Pharm, M.Tech (BioEngg), PhD3 years ago
Shubhankar Kulkarni Thank You Mr. Kulkarni !!

I appreciate your interest in this topic and I am happy to have your questions and comments.

Both the questions are excellent ones. Thank you very much.

We don't know the answers. It is absolutely worthwhile to find answers to these questions.

I am really looking forward to many such fascinating brainstorming questions and comments as yours.

Please leave the feedback on this idea