Perioperative, Spatiotemporally Coordinated Activation of T and NK Cells Prevents Recurrence of Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T-cell activation was confirmed by increased tumor infiltration with CD103CD8 T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK-cell checkpoint CD96, an inhibitory NK-cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease. Coordinated neoadjuvant and adjuvant immunotherapies reduce the risk of disease relapse after resection of murine PDAC, suggesting this concept for future clinical trials. .

The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor‐infiltrating T cells

“…Recent preclinical studies have identified CD96 and TIGIT as co‐inhibitory Ig superfamily receptors which function on lymphocytes to counterbalance the costimulatory CD226. CD226 plays a dominant and central role in NK and T‐cell‐mediated antitumor immunity and recent murine work supports an inhibitory role for CD96 . The functional interplay between the activating CD226 and the inhibitory CD96 and TIGIT receptors is reminiscent of the CTLA‐4/CD28 counterbalance that is critical for the fine tuning of the immune response to cancer .…”

“…CD226 plays a dominant and central role in NK and T-cell-mediated antitumor immunity 3,20 and recent murine work supports an inhibitory role for CD96. 21 The functional interplay between the activating CD226 and the inhibitory CD96 and TIGIT receptors is reminiscent of the CTLA-4/CD28 counterbalance that is critical for the fine tuning of the immune response to cancer. 22 Demonstration of TIGIT expression and function in infiltrating T cells from human tumors 10 has provided evidence for the translational potential for this pathway in cancer treatment; however, similar expressional validation of CD96 in human immune cells has limited any translational progression of this target.…”

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single‐agent checkpoint blockade

“…Gemcitabine with delayed anti-PD-L1 therapy (≥ 14 days after gemcitabine) and gemcitabine with simultaneous PD-L1 blockade showed enhanced tumor suppression compared to either modality alone; however, only simultaneous combination therapy resulted in complete responses (CRs) in treated mice [4]. In a transgenic mouse model of resectable PDAC, neoadjuvant PD-1 inhibition and gemcitabine significantly reduced local recurrence and improved survival compared to either modality alone, while promotion of natural killer (NK) cell activation with the addition of anti-CD96 antibody to adjuvant gemcitabine enhanced control of distant metastases [15]. This preclinical model therefore highlighted the potential of combination strategies with PD-1 blockade to target acquired resistance (preventing recurrence) in addition to the more commonly investigated goal of enhancing response to PD-1 inhibition (targeting primary resistance).…”

“…MEK mitogen-activated protein kinase (MAPK) kinase; IL-18 interleukin 18, IL-6R interleukin 6 receptor, mAb-AR20.5 anti-MUC1, PolyICLC toll like receptor-3 ligand, BAG3 Bcl-2-Associated athanoGene 3, IFNγ interferon-γ, CCK cholecystokinin [15] colony-stimulating factor 1 receptor (CSF1R) decreased TAMs and reprogrammed TAMs to promote antigen presentation and antitumor T cell activity, increased CD3+CD8+ cytotoxic T-lymphocytes (CTLs) and CD3+CD4+ effector T-cells, decreased CD4+Foxp3+ Tregs, improved the effector T-cell/Treg ratio, and upregulated PD-L1 and CTLA-4 on PDAC cells. Combination CSF1/CSF1R and PD-1 or CTLA-4 blockade synergistically restrained tumor progression, compared to controls.…”

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

“…Our understanding of the underlying factors which contribute to disease recurrence following surgery is currently limited by the paucity of immunocompetent preclinical models of surgically resectable PDAC. The potential of such models to provide critical insights has been elegantly demonstrated in two recent publications which characterize the impact of (neo)adjuvant chemotherapy treatment on the immune system and tumor growth following surgical resection 5,6 . However, widespread implementation of this model may be limited by the challenges associated with acquiring and maintaining the transgenic mouse strain and the in vivo electroporation procedures needed for initiating tumor growth.…”