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.
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
(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?
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.
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
1: Tumor-extrinsic Immune Evasion in the Tumor Microenvironment (2018, May 17). Technology
Networks: Exploring the Science that Matters to You
https://www.technologynetworks.com/tn/articles/tumor-extrinsic-immune-evasion-in-the-tumor-microenvironment-302929
2: Gene variation promotes uncontrolled cell division (2016, Dec 16). Max-Planck-Gesselschaft
https://www.mpg.de/9804265/krebs-stat3
https://www.jci.org/articles/view/96708/sd/2
https://www.traps-vari.org/weblog/
ViJay K. U. Nathan; B.Pharm, M.Tech (BioEngg), PhD Feb 21, 2021