# In situ radioimmunotherapy to maximize the engagement of conventional type 1 dendritic cells against non-T cell-inflamed tumors

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2021 · $410,221

## Abstract

Radiation therapy (RT) is known to exert direct cytotoxic effects on tumor cells; however, recent research is
revealing its influence on the immunogenicity of tumors, thus affecting the overall outcome of RT. While RT
alone is usually insufficient to overcome the immunosuppressive tumor microenvironment (TME), strategies to
boost immune-stimulating effects of RT are under intensive investigation. To date, most of the focus has been
placed on immunomodulation after RT, in particular in combination with immune checkpoint inhibitors. Little is
known about how manipulation of the TME before RT can impact on immunogenicity and therapeutic efficacy of
RT. A growing body of evidence reveals that Batf3-dependent conventional type 1 dendritic cells (cDC1) rarely
found within the tumor myeloid compartment have the important capacity of cross-presenting tumor-associated
antigens (TAA) to CD8+ T cells, and act as `master regulators' for the T cell response in cancer. We hypothesize
that in situ induction and activation of cDC1 enhances the therapeutic efficacy and immunogenicity of RT. To
test this hypothesis, we developed a combinatorial in situ radioimmunotherapy comprised of in situ administration
of: 1) Flt3L to mobilize cDC1 to the TME; 2) RT to promote immunogenic death of cancer cells and maturation
of DC; and 3) dual TLR3/CD40 stimulation to activate antigen-loaded cDC1 for priming of tumor-specific CD8+ T
cells. Our new data using multiple syngeneic orthotopic murine models of poorly immunogenic tumors
insensitive to anti-PD-L1 therapy reveal that in situ radioimmunotherapy elicits de novo adaptive T cell responses
that are characterized by novel clonotypes and stem-like Tcf1+ Slamf6+ phenotypes, renders tumors responsive
to anti-PD-L1 antibody, mediates durable complete responses, and develops tumor-specific systemic
immunological memory. Compelling evidence suggests that immunogenicity of RT can be enhanced by in situ
induction and activation of cDC1; however, immunomodulatory effect of in situ radioimmunotherapy against
distant metastatic tumors remains unclear. cDC1 prime CD4+ T cells as well as CD8+ T cells, but the role of CD4+
T cells in in situ radioimmunotherapy remains elusive. In addition, it remains unknown whether in situ
radioimmunotherapy overcomes poor T-cell infiltration in human non-T cell-inflamed tumors. In this proposal
we will elucidate the roles of CD4+ T cells in augmenting antitumor efficacy of in situ radioimmunotherapy (Aim
1). Additionally, we will seek to better understand the mechanisms underlying the immunomodulatory effect of
in situ radioimmunotherapy targeting non-irradiated distant metastatic tumors (Aim 2). Finally, in Aim 3, we will
seek to determine the alteration of the human TME in patients with unresectable and metastatic breast cancer
treated with in situ radioimmunotherapy. These studies will add essential mechanistic understanding to how RT
and the immune system interact, and provide insight into the clini...

## Key facts

- **NIH application ID:** 10297983
- **Project number:** 1R01CA255240-01A1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Fumito Ito
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,221
- **Award type:** 1
- **Project period:** 2021-08-01 → 2021-12-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297983

## Citation

> US National Institutes of Health, RePORTER application 10297983, In situ radioimmunotherapy to maximize the engagement of conventional type 1 dendritic cells against non-T cell-inflamed tumors (1R01CA255240-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297983. Licensed CC0.

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