Drivers of Spatial Immune Heterogeneity in a Mouse Tumor Model after Immunotherapy

21 Pages Posted: 11 Jun 2024

See all articles by Michal Smahel

Michal Smahel

Charles University

Shweta Dilip Johari

Charles University

Jana Smahelova

Charles University

Lucie Pfeiferova

affiliation not provided to SSRN

Jaroslav Nunvar

Charles University

Abstract

Introduction: Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. Methods: The study investigated spatial immune heterogeneity in the tumor microenvironment and its drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. Results: A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. Immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated homologous recombination and translesion synthesis genes. While the total number of mutations was comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with extracellular matrix metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, toll-like receptor cascades, and cytokine production. Conclusions: This study highlights intratumoral immune heterogeneity as a cause of tumor immune escape and suggests the mechanisms involved.

Note:
Funding declaration: This work was supported by the Czech Science Foundation, grant number GA19-00816S; the European Union—Next Generation EU—the project National Institute of Virology and Bacteriology (the program EXCELES), grant number LX22NPO5103; Charles University, grant numbers SVV 260679; and the League against Cancer Prague.

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: Animal protocols were approved by the Sectoral Expert Committee of the Czech Academy of Sciences for Approval of Projects of Experiments on Animals (reference number 69/2018, 13 August 2018).

Keywords: mutation, DNA repair, cancer immunotherapy, intratumoral heterogeneity, tumor microenvironment, translesion synthesis

Suggested Citation

Smahel, Michal and Johari, Shweta Dilip and Smahelova, Jana and Pfeiferova, Lucie and Nunvar, Jaroslav, Drivers of Spatial Immune Heterogeneity in a Mouse Tumor Model after Immunotherapy. Available at SSRN: https://ssrn.com/abstract=4855460 or http://dx.doi.org/10.2139/ssrn.4855460

Michal Smahel (Contact Author)

Charles University ( email )

U Knize 8
Prague, 15800
Czech Republic

Shweta Dilip Johari

Charles University ( email )

U Knize 8
Prague, 15800
Czech Republic

Jana Smahelova

Charles University ( email )

U Knize 8
Prague, 15800
Czech Republic

Lucie Pfeiferova

affiliation not provided to SSRN ( email )

No Address Available

Jaroslav Nunvar

Charles University ( email )

U Knize 8
Prague, 15800
Czech Republic

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