Biology subjects

Humblin, E.

Publications and source records attributed to Humblin, E..

5 recordsLinked to original sources

bioRxiv2026

B cells sustain tumor-specific CD4 T cells to promote response to PD-1 targeted therapy

Immunotherapy transformed cancer treatment, yet precise correlates of response remain to be defined. While intratumoral follicular helper like (Tfhl) CD4 T cells and IgG1+ B cells have been associated with improved outcomes to PD-1 blockade for hepatocellular carcinoma (HCC), their mechanisms contributing to response are unclear. To address this question, we developed a murine model of HCC and examined CD8, CD4 and B cell responses. Increasing CD4-help sensitizes mice to PD-1 blockade, in a CD4- and CD8-dependent manner. Tumor-specific CD4 T cells contained Tfhl and Th1 populations, and both Bcl6 and T-bet were required for efficacy. Antigen-specific B cells were essential for CD4-helper expansion, yet secretion of antibodies was not required for long-term survival. Thus, B cells are critical for effective immunotherapy, but secreted antibodies are not.

immunology↗

bioRxiv2024

Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoidstructures in cancer

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFN{gamma}-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.

immunology↗

bioRxiv2024

ICOS limits memory-like properties and function of exhausted PD-1+ CD8 T cells

During persistent antigen stimulation, PD-1+CD8 T cells are maintained by progenitor exhausted PD-1+TCF-1+CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1+CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory-like features of Tpex. In mice with established chronic infection, ICOS-Ligand blockade resulted in expansion of effector-like Tex and reduction in viral load. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1+CD8 T cells and delayed tumor growth. Overall, we show that ICOS limits CD8 T cell responses during chronic antigen exposure.

immunology↗

bioRxiv2024

Functional impairment of "helpless" CD8+ memory T cells is transient and driven by prolonged but finite cognate antigen presentation

Generation of functional CD8+ T cell memory typically requires engagement of CD4+ T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (TE) and subsequent memory (TM) CD8+ T cell formation appear impervious to a lack of CD4+ T cell help during priming. Nonetheless, such "helpless" CD8+ TM respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8+ T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8+ TE differentiation is largely normal but a multiplicity of helpless CD8 TM defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8+ TM potential and recall capacity. Our findings provide a unified explanation for helpless CD8+ T cell memory and emphasize an unexpected CD8+ TM plasticity with implications for vaccination strategies and beyond.

immunology↗

bioRxiv2022

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.

immunology↗