46: A novel mechanism of immunotherapy sensitivity following platinum chemotherapy resistance in pancreatic cancer patients with germline homologous recombination deficiency

Thursday, March 21, 2024

2:42pm – 2:52pm ET

Location: C101

Abstract Presenter(s)

Ifeanyichukwu Ogobuiro, MD, MHS

T32 Surgical Oncology Research Fellow/Radiation Oncology Resident
University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center
MIAMI, Florida, United States

Submitter(s)

Ifeanyichukwu Ogobuiro, MD, MHS

T32 Surgical Oncology Research Fellow/Radiation Oncology Resident
University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center
MIAMI, Florida, United States

Author(s)

Ifeanyichukwu Ogobuiro, MD, MHS

T32 Surgical Oncology Research Fellow/Radiation Oncology Resident
University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center
MIAMI, Florida, United States
KR

Karthik Rajkumar, PhD

Post-Doc
University of Miami, United States
Anna Bianchi, PhD

Computational and Cancer Biology Scientist
University of Miami School of Medicine - Miami, FL
Miami, Florida, United States
LC

Lucas Caeiro, PhD

Post-Doc
University of Miami School of Medicine - Miami, FL, United States
Haleh Amirian, MD, MS

Post-Doc
University of Miami School of Medicine - Miami, FL, Florida, United States
LN

Luis Nivelo, MS

PhD Candidate
University of Miami School of Medicine - Miami, FL, United States
ID

Iago De Castro Silva, MD

Surgery Resident
University of South Florida, United States
AA

Andrew Adam, MS

PhD Candidate
University of Miami School of Medicine - Miami, FL, United States
VG

Vanessa Garrido, PhD

Post-Doc
University of Miami School of Medicine - Miami, FL, United States
SS

Samara Singh, BS

PhD Candidate
University of Miami School of Medicine - Miami, FL, United States
NN

Nagaraj Nagathihalli, PhD

Research Associate Professor
University of Miami School of Medicine - Miami, FL, United States
NM

Nipun B. Merchant, MD

Surgical Oncologist
Department of Surgery, University of Miami, United States
RV

Ramiro Verdun, PhD

Research Professor
University of Miami School of Medicine - Miami, FL, United States
Jashodeep Datta, MD (he/him/his)

Assistant Professor of Surgery
Department of Surgery, University of Miami Sylvester Comprehensive Cancer Center
Pinecrest, Florida, United States

Disclosure(s):

Ifeanyichukwu Ogobuiro, MD, MHS: No financial relationships to disclose

Haleh Amirian, MD, MS: No financial relationships to disclose

Jashodeep Datta, MD: Cantargia AB, Inc: Research Grant (Ongoing)

Introduction:

Platinum chemotherapy is standard of care for treatment of pancreatic ductal adenocarcinoma (PDAC) arising in patients with germline mutations in homologous recombination genes (mutHRD). We recently reported that mutHRD PDAC patients progressing on platinum chemotherapy respond to dual immune checkpoint blockade (ICB) with anti-PD1+CTLA-4. We modeled these clinical findings in preclinical systems to interrogate mechanisms in platinum-resistant mutHRD PDAC that drive ICB sensitivity.

Methods:

We examined association between objective disease response following ICB and duration of platinum chemotherapy exposure in mutHRD PDAC patients. To model platinum-resistant mutHRD PDAC in vitro and in vivo, we generated cisplatin- resistant and sensitive Brca2-silenced KPC cancer cells (shBrca2) and characterized these via whole transcriptome sequencing (WTS) and single-cell RNA sequencing (scRNAseq), respectively.

Results: In 12 platinum-resistant mutHRD patients, duration of prior platinum exposure was associated with post-ICB disease response in 7 (58%). To model this preclinically, mice implanted with cisplatin-sensitive or resistant shBrca2 KPC tumor cells and subsequently treated with gemcitabine+cisplatin demonstrated expected rapid tumor growth of cisplatin-resistant shBrca2 tumors. However, we observed a profound reduction in tumor volumes when cisplatin-resistant KPC-shBrca2 tumors were treated with dual anti-PD-1+CTLA4 ICB, compared to cisplatin-sensitive KPC-shBrca2 tumors (P< 0.001). Mechanistically, WTS revealed significant differential upregulation of type1 interferon and STING pathways in cisplatin-resistant vs. -sensitive KPC-shBrca2 tumor cells in vitro (P-adj≤0.05). scRNAseq following gemcitabine+cisplatin treatment in vivo showed enrichment of STING signaling in tumor cell compartment (Figure). Confocal imaging confirmed constitutively upregulated STING expression in cisplatin-resistant KPC-shBrca2. This manifested a secretome enriched for T-cell trafficking cytokines CXCL10, CXCL9, and CCL5 in cisplatin-resistant KPC-shBrca2 cells. Intriguingly, evaluable mutHRD patient tumors responsive to dual ICB also demonstrated increased CXCL9/10 and CCL5 expression vs ICB-resistant tumors via Nanostring analysis. We observed increased trafficking of CD4/CD8 T-cells with less dysfunctional transcriptomes via scRNAseq into cisplatin-resistant KPC-shBrca2 tumors in vivo.

Conclusions:

Chronicity of platinum exposure in mutHRD PDAC potentiates ICB sensitivity via induction of cell-autonomous STING signaling and ensuing T-cell trafficking to the PDAC tumor microenvironment.

Learning Objectives:

Decipher subset of HRD-mutant PDAC patients that benefit from dual immune check-point blockade.
Learn about the development of murine model that recapitulates the clinical phenotype seen in HRD-mutant PDAC patients that are resistant to standard of care platinum-based therapy.
Understand the mechanism that drive sensitivity to dual immune check-point blockade in HRD-mutant PDAC patients that are resistant to standard of care platinum-based therapy.