Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer
Mahadevan K.K. et al. (BioRxiv) DOI: 10.1101/2023.03.05.531191
Antigen-presenting type-I conventional dendritic cells
Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to immune checkpoint blockade (ICB), possibly due to various factors, including low mutational burden and an exceptionally hostile tumor microenvironment that is characterized by a high abundance of tumor stroma, suppressive myeloid and regulatory T cells, together with a lack of professional antigen presenting cells (APCs). Additionally, whether pre-existing or onset of pancreatitis contribute to PDAC is still unknown. In this study, the authors investigated the crosstalk between pancreatitis, the immune landscape of PDAC, and therapeutic responses to immune checkpoint blockade.
Proteomic analysis of inflamed pancreases from non-tumour bearing mice showed increased infiltration of cDCs and myeloid cells with reduced infiltration of T cells in pancreatic lymphoid structures. This phenotype was partially recapitulated in an additional model of PDAC following pancreatitis induction (KC mice model), which was also associated with accelerated tumour initiation and increased tumour growth.
Interestingly, depleting CD4+T cell in these mice suppressed tumor development and increased overall survival, an effect that was abrogated by co-depleting either CD8+ T cells or CD11c+ dendritic cells. Further histologic analyses revealed that CD4+ T cell depletion in KC mice with pancreatitis increased the proximity of CD8+ T cells to CD11c+ cells, suggesting that CD4+T cells restrain cDC priming of anti-tumoral CD8+ T cells in pancreatitis associated PDAC.
Ultimately, the authors show that pancreatitis rendered PDAC-bearing mice sensitive to ICB, which was associated with increased infiltration of activated CD8+ T cells. Importantly, this sensitization to ICB led to durable curative outcomes that could be recapitulated in PDAC-bearing mice without pancreatitis when combining ICB and vaccination with cDC1 loaded with tumor lysate, both in a preventive and therapeutic manner, highlighting a crucial role for cDC1s in enabling responses to ICB in PDAC.
The authors show that pancreatitis in both non-tumour bearing and tumour-bearing mice leads to increased infiltration of myeloid cells (Fig. 1.G, Supplementary figure 1.E-F, Supplementary figure 2.G, Supplementary figure 7.D). It would have been interesting to examine their role in these models and the contribution of these pancreatitis-associated myeloid cells to disease progression and treatment outcome. One obvious question is whether these myeloid cells represent an immunosuppressive immune subset, the existence of which has been well documented in PDAC.
Additionally, one might wonder if other types of pancreatic inflammation would lead to similar findings: although the authors study and thoroughly compare short-term and long-term pancreatitis, both are induced through caerulein injections.
While the authors show that pancreatitis leads to a mild infiltration of cDC1s (Fig. 2.K) and suggest that this contributes to the sensitization to ICB, similarly as the use of cDC1-based vaccines, the mechanisms underlying how pancreatitis-associated cDC1s leads to anti-tumoral T cell responses would have been valuable. To truly address this question, it should be studied if specific depletion of cDC1 cells from PDAC-bearing mice with pancreatitis would abrogate the sensitivity to ICB.
This study sheds new light on the role of pancreatitis in remodelling the PDAC immune landscape and on the key cellular determinants for clinical responses to ICB. Moreover, it highlights the potential therapeutic importance of combining ICB with cDC1 vaccines in PDAC, and perhaps in other types of cancers.
PDAC is an undeniably lethal and treatment-refractory cancer. This study informs us on possible therapeutic approaches with curative outcomes in immunotherapy-resistance models of this cancer, approaches which are encouraging both for the field and PDAC patients.
Reviewed by Lucas Baldran-Groves 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.