IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation

ABSTRACT

Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth.

KEYWORDS:

• cancer
• IL-1 family
• IL-38
• inflammation
• innate immunity

Abbreviations

IL-38, interleukin 38; IL1RAPL1, interleukin 1 receptor accessory protein-like 1; IL-36R, interleukin 36 receptor; HNSC, head and neck squamous carcinoma; CESC, cervical squamous carcinoma; LUSC, lung squamous cell carcinoma; TCGA, The Cancer Genome Atlas; IV, intravenous; IP, intraperitoneal; QW, weekly dosing; Q2W, twice-weekly dosing.

Acknowledgments

The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Disclosure statement

Authors are employees and shareholders of Immunome, Inc. The described antibodies and data have been included in patent applications.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2023.2212673

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.