Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

Abstract

The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.

Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

“…Moreover, in a MC38 tumor model, response to anti-PD-1 was dependent on intratumoral cDC1 production of CXCL9 and subsequent signaling through CXCR3 on T cells, which promoted proliferation and production of IFNγ, TNFα, and Granzyme B ( 175 ). In a breast cancer model, expansion of adoptively transferred tumor antigen-specific T cells was mediated by DC engagement through a combination therapy of Flt3L, radiotherapy, poly(I:C), and a CD40 agonist ( 176 ). Adoptive transfer of CAR T cells engineered to secrete Flt3L and in combination with poly(I:C) and anti-4-1BB enhanced T cell and DC expansion and activation in various tumor models ( 177 ).…”

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

“…The crucial role of CD103 + cDC1s was further demonstrated in Batf3 −/− mice lacking CD103 + cDC1s, which fail to reject tumors and do not respond to immune checkpoint inhibition [ 28 , 29 ]. Given the importance of cDC1s in cancer immunity, several authors have focused their efforts on attempting to recall cDC1s within the tumor site, thereby promoting subsequent CD8 + T cell recruitment and efficient control of tumor growth [ 30 , 31 ].…”

“…FLT3L binds DCs by inducing their proliferation, differentiation, development and mobilization. Administration of FLT3L in combination with radiotherapy to promote immunogenic tumor cell death and maturation of DCs, and dual TLR3/CD40 stimulation to activate antigen-loaded cDC1 for priming and expansion of tumor-specific CD8 + T cells, has been shown to enhance tumor immunity in several mouse models [ 30 ]. These encouraging results have led the Food and Drug Administration (FDA) to approve the use of human recombinant FLT3L (CDX-301) in the clinic for multiple tumors.…”

“…This clinical trial was followed by others currently on going in patients with breast cancer and head and neck squamous cell carcinoma (NCT03789097), as well as with non-small cell lung cancer and lung cancer (NCT04491084) ( Table 2 ). The addition of anti-CD40 antibody to FLT3L, radiotherapy and Poly-ICLC has been shown to induce regression of poorly T cell-infiltrated tumors refractory to PD-1/PD-L1 therapy in four syngeneic mouse models: colon adenocarcinoma, melanoma and two triple-negative mammary cancers of melanoma [ 30 ]. Interestingly, this treatment increases the infiltration of CD8 + T cells that mediate the regression not only of primary, but also of untreated distant tumors poorly infiltrated by T cells [ 30 ].…”

“…The addition of anti-CD40 antibody to FLT3L, radiotherapy and Poly-ICLC has been shown to induce regression of poorly T cell-infiltrated tumors refractory to PD-1/PD-L1 therapy in four syngeneic mouse models: colon adenocarcinoma, melanoma and two triple-negative mammary cancers of melanoma [ 30 ]. Interestingly, this treatment increases the infiltration of CD8 + T cells that mediate the regression not only of primary, but also of untreated distant tumors poorly infiltrated by T cells [ 30 ]. These very encouraging results were followed by a Phase I clinical trial initiated on December 1th, 2020 to evaluate the safety of in situ immunomodulation with recombinant CDX-301, radiotherapy, anti-CD40 mAb and Poly-ICLC in patients with unresectable and metastatic breast cancer (NCT04616248).…”