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Localized PD-1 Blockade in a Mouse Model of Renal Cell Carcinoma
Ngoc B Pham1, Nevil Abraham1, Ketki Y Velankar1
1Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States.
Abstract:
Herein we report the impact of localized delivery of an anti-mouse PD-1-specific monoclonal antibody (aPD1) on Renca tumors in the resulting T cell responses and changes in broader immune gene expression profiles. Renca is a BALB/c mice syngeneic tumor that has been used to model human renal cell carcinoma In this study, T cell subsets were examined in tumors and draining lymph nodes of mice treated with localized PD-1 with and without the addition of adenosine deaminase (ADA), an enzyme that catabolizes adenosine (ADO), identified as an immune checkpoint in several types of human cancers. The biologics, aPD1, or aPD1 with adenosine deaminase (aPD1/ADA), were formulated with the self-assembling peptides Z15_EAK to enhance retention near the tumor inoculation site. We found that both aPD1 and aPD1/ADA skewed the local immune milieu towards an immune stimulatory phenotype by reducing Tregs, increasing CD8 T cell infiltration, and upregulating IFNɣ. Analysis of tumor specimens using bulk RNA-Seq confirmed the impact of the localized aPD1 treatment and revealed differential gene expressions elicited by the loco-regional treatment. The effects of ADA and Z15_EAK were limited to tumor growth delay and lymph node enlargement. These results support the notion of expanding the use of locoregional PD-1 blockade in solid tumors.
Insights
Localized anti-PD-1 antibody therapy enhanced anti-tumor immunity in Renca mouse models by reducing regulatory T cells and increasing CD8 T cell infiltration. This approach shows promise for treating solid tumors.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Renal cell carcinoma (RCC) is modeled using Renca tumors in BALB/c mice.
- Adenosine (ADO) is an immune checkpoint in various human cancers.
- PD-1 blockade is a key immunotherapy strategy.
Purpose of the Study:
- To investigate the impact of localized anti-mouse PD-1 antibody (aPD1) delivery on Renca tumors.
- To assess T cell responses and immune gene expression profiles.
- To evaluate the combination of aPD1 with adenosine deaminase (ADA).
Main Methods:
- Localized delivery of aPD1 and aPD1/ADA formulated with self-assembling peptides (Z15_EAK).
- Analysis of T cell subsets (Tregs, CD8 T cells) in tumors and lymph nodes.
- Bulk RNA-sequencing (RNA-Seq) of tumor specimens.
- Assessment of tumor growth and lymph node size.
Main Results:
- Both aPD1 and aPD1/ADA treatments reduced Tregs and increased CD8 T cell infiltration and IFNɣ.
- Localized aPD1 treatment modulated the local immune microenvironment towards immune stimulation.
- RNA-Seq confirmed differential gene expression induced by loco-regional aPD1.
- ADA and Z15_EAK showed limited effects on tumor growth delay and lymph node enlargement.
Conclusions:
- Localized PD-1 blockade effectively enhances anti-tumor T cell responses.
- The combination therapy warrants further investigation for solid tumor treatment.
- Locoregional PD-1 blockade is a promising strategy for expanding immunotherapy applications.
