24 nov. 2025
Li, Z et al. (BioRxiv)
Keywords
Somatic Mutation
T cells
Tumor Infiltrating lymphocytes.
Interferon signalling
Main Findings
As one age over time, there is an increase in the frequency of hemopoietic stem cells (HSC) with somatic mutations. These mutations can potentially affect the fitness of the HSC either debilitating or increasing their renewal which after receiving differentiation signal can undergo malignant transformation, induce myeloid bias, and increase inflammation. These mutations are often called Clonal Hematopoiesis of Indeterminate Potential (CHIP), and they affect risks of multiple blood cancer such as leukemia and has been associated with risk of inflammation in cardiac and neurologic diseases, however recently, more focus has been redirected to their role in solid tumors and altering response to immune checkpoint blockade. The immune compartment carrying these mutations are predominantly myeloid cells. However, as this study shows T cells can have somatic mutations and these mutations are enriched in tumor infiltration lymphocytes across multiple cancer types including melanoma, colon cancer and non-small cell lungs cancer. Using whole-exome nano sequencing, a duplex sequencing approach that is sensitive to low variant allele frequencies within a heterogenous cell population. The authors identified multiple somatic mutations in the Tyk2 protein, only in T cells and little to none in other lymphocytes like B cells and NK cells. Using preclinical in-vitro and murine models, the authors showed that a certain Tyk2 point mutation (at position 810 in humans and 807 in mice) increases T cell quality without inducing any debilitating autoimmune or haematological cancer risks. In a tumor context, the authors showed better tumor control in the mice with a homozygous or heterozygous Tyk2 mutation and this effect is greater with immunotherapy.
Limitations
Patient information: Lack of data on if they are treatment naïve or received therapy.
Mutations: The authors did mention about other mutations (TABLE S1), however, since we are not provided the table, it would be nice to state in the text the allele frequency of TyK2 mutation. The authors did not mention any possibility of single T cells having multiple somatic mutations and why focus on the Tyk2 if there are other mutations. Maybe bring line 154-157 up to suggest why the focus on Tyk2 mutations.
Although the authors did 12 months analysis of both lymphoid and non-lymphoid tissue to show no difference between mutant and wild type (WT) littermates of the mice. 12 months in mice is corresponds to 38–47-year-old human, but some haematological malignancies particular leukemia occurs at 60 years and above, which is 18-24 months in mice which would be the sweet spot to really check risks of certain inflammatory conditions, dependent and independent of aging.
Distribution of mutations in the CD4 versus the CD8 T cells compartments. As CD4+ T cells and CD8 T cells have the same progenitors (thymocytes), the authors need to discuss why certain mutations seems exclusive to each and if this mutation affects the fitness of each T cell during thymic education.
In the preclinical tumor model, the authors showed that the protectiveness seen in the mice model is CD8 T cell dependent however there was no presence of this mutant in the human CD8+ T cell nanoseq. It seems to be present in CD4+ T cells only and does not really represent the mutations found in the humans.
The authors show there’s an increase of IFNAR and IFN gamma signaling in the T cells (Figure 1) but did not block each signal in the tumor context to directing implicate Type I or II interferons in inducing this effect.
As all T cells have these mutations, the authors need to dive deeper into the effector versus the memory effect, looking at the proportions in the population does not really inform us on the quality or the functionality of the cells, this can be tested with a rechallenge (for memory) due to the subcutaneous model (surgery). Additionally, TyK2 is important in broad cytokine response, access the mutation effect on cytokine function beyond IL-12 such as in IL-10 and in other T cell subsets like regulatory T cells.
Multiple studies (PMID: 31398344, 27912061) have shown that chronic Interferon signalling leads to T cell exhaustion, the authors need to show the exhaustive capabilities in TyK2 mutated T cells versus the wildtype and if shows less exhaustion, explain why this is occurring compared to the classical thoughts.
Since Patients samples were used to derive the mutations, it would be interesting to look phenotypically the T cells in these patients compared to patient without such mutation. Can a signature module be generated from T cells with this mutation and applied to predicting T cell response?
The authors showed data that TyK2 mutations in HCC intrinsically control tumor growth, however, is this immune dependent? It must be performed in a RAGKO/NSG setting to support the hypothesis. Additionally, it would be nice to see the Immune populations in this mutated HCC tumors versus WT. By doing this autochthonous, they are suggesting possible germline mutation which is not strongly supported by the T cell specific Tyk2 mutants.
Similarly, would be stronger to explore both intrinsic and extrinsic control of this mutation to do their hydrodynamic model in a WT host (transplanted with bone marrow from Tyk2 D807V mutant mice) and vice versa.
Although the author performed inhibition of Tyk2 has a confirmation test of its importance in T cell mediated anti-tumor immunity. It would be nice to show if promoting Tyk2 signalling by pharmalogical inhibition of SOCS1, SOCS3, PTPN1 or SHP1 if it promotes tumoricidal effects as a therapeutic option in patients that lack these beneficial mutations.
Advances in JAK1 inhibition combined with ICI shows beneficial effect (PMID: 38900877). Need to do combo of deucravacitinib with anti PDL1 blockade to refute the claims: Deucravacitinib: details on injection timeline missing, need to clarify more on possibility of temporal inhibition could affect anti-tumor immunity.
Significance/Novelty
Somatic mutations presence in immune populations have been solely studied in the myeloid compartments. This preprint by Zhijie Li et al. changes the notions that T cell mutations stays the same throughout lifetime, but the possibility that not all T cells are equal at the genomic level which would affect the phenotypic effect leading to differential responses to immunotherapy. The study strongly shows that certain mutated T cells are enriched in tumors and warrants more investigation. This idea can influence future development of CAR and TCR-T cells that would lay groundwork of long-term tumor control in these therapies.
Credit
Reviewed by Ezekiel Olumuyide as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute, and the University of Toronto.
The author declares no conflict of interests in relation to their involvement in the review.