Sobti, A. | bioRxiv Science

bioRxiv2025

Differential Impact of Lymphocytes on Radiation Response in Autochthonous versus Transplant Sarcomas in Syngeneic Mice

Preclinical studies in transplant tumor models showing high cure rates with combined radiotherapy (RT) and immunotherapy have rarely translated to clinical success, and studies in autochthonous tumor models are limited. We hypothesized that lymphocytes differentially affect RT response in transplant versus autochthonous tumor models. Here, we compared tumor onset and growth delay after 0 or 20 Gy for autochthonous versus transplant soft tissue sarcomas in Rag2-/- mice lacking an adaptive immune system versus immune-intact Rag2+/- mice. While time to tumor onset did not differ between Rag2-/- and Rag2+/- mice in the autochthonous model, transplant tumor onset was significantly slower in immunocompetent mice. No transplant tumors in Rag2-/- mice or autochthonous tumors were cured by RT, whereas 30.4% of Rag2+/- mice with transplant tumors were cured. These results highlight the importance of including autochthonous tumors as complementary model systems to study the interplay between the immune system and RT response.

cancer biology↗

bioRxiv2022

Single-cell analysis of myeloid cells in HPV+ tonsillar cancer

The incidence of Human Papillomavirus positive (HPV+) tonsillar cancer has been sharply rising during the last two decades. Myeloid cells represent an appropriate therapeutic target due to their ability to orchestrate antigen-specific immunity within the tonsil, the availability of viral antigens, and the proximity of the tumor and the underlying lymphoid tissue. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. Our analysis unveiled the existence of four dendritic cell lineages, two macrophage polarization processes, and their sequential maturation profiles. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in DCs and monocyte-macrophages. Within the DC lineages, we describe a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s, in HPV+ lesions. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC profile. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which gave raise to inflammatory-activated, and chemokine-producing macrophages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1, activated DCs and macrophages in patient survival using signature scoring. The current study contributes towards the understanding of myeloid ontogeny and dynamics in human papilloma driven tonsillar cancer, and details myeloid biomarkers that can be used to predict therapy effects and assess patient prognosis.

immunology↗