Cohen, E. E. W. | Search bioRxiv

bioRxiv2023

Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

immunology↗

bioRxiv2022

Lymphatic-Preserving Treatment Sequencing with Immune Checkpoint Inhibition Unleashes cDC1-Dependent Antitumor Immunity in HNSCC

Immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 has revolutionized oncology; however, response rates remain limited in most cancer types, highlighting the need for more effective immune oncology (IO) treatment strategies. Paradoxically, head and neck squamous cell carcinoma (HNSCC), which bears a mutational burden and immune infiltrate commensurate with cancers that respond robustly to ICI, has demonstrated no response to anti- CTLA-4 in any setting or to anti-PD-1 for locally-advanced disease. Scrutiny of the landmark clinical trials defining current IO treatments in HNSCC reveals that recruited patients necessarily received regional ablative therapies per standard of care, prompting us to hypothesize that standard therapies, which by design ablate locoregional lymphatics, may compromise host immunity and the tumor response to ICI. To address this, we employed tobacco-signature HNSCC murine models in which we mapped tumor-draining lymphatics and developed models for regional lymphablation with surgery or radiation. Remarkably, we found that lymphablation eliminates the tumor ICI response, significantly worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observed an upregulation of cDC1 cells and IFN-I signaling, showed that both are necessary for the ICI response and lost with lymphablation. Ultimately, we defined rational IO sequences that mobilize peripheral immunity, achieve optimal tumor responses, confer durable immunity and control regional lymphatic metastasis. In sum, we provide a mechanistic understanding of how standard regional, lymphablative therapies impact the response to ICI, which affords insights that can be applied to define rational, lymphatic-preserving IO treatment sequences for cancer. One Sentence SummaryDespite the promise of immune checkpoint inhibition, therapeutic responses remain limited, raising the possibility that standard of care treatments delivered in concert may compromise the tumor response; here, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, confer durable antitumor immunity, and control regional metastatic disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/478744v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@542d71org.highwire.dtl.DTLVardef@737ad0org.highwire.dtl.DTLVardef@183f519org.highwire.dtl.DTLVardef@505ce2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity ([≤]20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 ([≤]20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC.

cancer biology↗