# Project 3: Myeloid-lymphoid cell crosstalk in HNSCC therapy

> **NIH NIH P01** · YALE UNIVERSITY · 2023 · $365,650

## Abstract

PROJECT SUMMARY
Some head and neck squamous cell carcinoma (HNSCC) patients see pronounced clinical responses with
immunotherapeutic intervention. These successes demonstrate the power of therapeutically (re-)activating
antitumor T cells to control cancer, but are insufficient, considering the many more patients who do not
experience clinical benefit when provided the same treatments. Increasing evidence shows two main barriers
to immunotherapy’s success against HNSCC: (i) the tumor’s often poor antigenicity, which limits the generation
of antitumor immunity, (ii) suppressive mechanisms that enforce immune tolerance within tumors. This P01’s
goal is to address these two barriers: Projects 1 and 2 aim to identify ways that increase HNSCC antigenicity;
this Project aims to direct enhanced antigenicity into a successful antitumor immune response. To this end, we
will harness myeloid cell populations and their crosstalk with T cells. When considering myeloid cells, we are
particularly interested in tumor-infiltrating dendritic cell (DC) populations, since they can present tumor-antigen
to T cells and license the execution of T cell-mediated tumor control. We will initially assess three drugs, which
we carefully chose based on their use in the clinic, their relevance to the other Projects, our initial data, and
their ability to target multiple tumor-associated components. Namely, we will study: (1) 5’azacytidine since it
augments tumor cell antigenicity in HNSCC patients and mice (see also Project 1); (2) anti-PD-1 mAb since it
can activate T cells to produce key antitumor cytokines such as IFN-gamma and is efficacious in some HNSCC
patients; (3) agonistic anti-CD40 mAb since it can induce a DC subset to produce the effector cytokine IL-12,
which fosters antitumor T cell activity. Therefore, these drugs may be rationally combined to promote tumor
control by targeting tumor cells, adaptive and innate immune cells simultaneously. We will also analyze other
drugs during the 5-year project, based in part on findings from Projects 1 and 2. To define drug effects on
myeloid⟷lymphoid cell crosstalk, we will leverage an ongoing clinical trial and animal models that recapitulate
key features of the human disease. We will also use two complementary single cell resolution approaches:
single cell RNA sequencing (scRNAseq) and single cell imaging (scIMAG). scRNAseq will provide an unbiased
view of drug-induced immune changes in human and mouse lesions, and permit comparison across species to
facilitate HNSCC translational research. scIMAG will provide information about drug-induced immune
responses over time and within the geographical context of the tumor. We hypothesize that these approaches
can identify mechanisms of drug-induced myeloid⟷lymphoid cell crosstalk, which are causally linked to
HNSCC control and can be harnessed for therapy. We should be well positioned to perform the proposed
work, having experience with studying immune cells and immunotherapy dru...

## Key facts

- **NIH application ID:** 10690603
- **Project number:** 7P01CA240239-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mikael PITTET
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $365,650
- **Award type:** 7
- **Project period:** 2019-09-19 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690603

## Citation

> US National Institutes of Health, RePORTER application 10690603, Project 3: Myeloid-lymphoid cell crosstalk in HNSCC therapy (7P01CA240239-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690603. Licensed CC0.

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