Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNg-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3ÀTNFa+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigenspecific T cells.

We develop an implicit discretization method for pricing European and American options when the underlying asset is driven by an infinite activity Lévy process. For processes of finite variation, quadratic convergence is obtained as the mesh and time step are refined. For infinite variation processes, better than first order accuracy is achieved. The jump component in the neighborhood of log jump size zero is specially treated by using a Taylor expansion approximation and the drift term is dealt with using a semi-Lagrangian scheme. The resulting Partial Integro-Differential Equation (PIDE) is then solved using a preconditioned BiCGSTAB method coupled with a fast Fourier transform. Proofs of fully implicit timestepping stability and monotonicity are provided. The convergence properties of the BiCGSTAB scheme are discussed and compared with a fixed point iteration. Numerical tests showing the convergence and performance of this method for European and American options under processes of finite and infinite variation are presented.

Background Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. Methods Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. Results This publication provides findings from the group’s discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. Conclusion Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

Pancreatic cancer is a particularly lethal malignancy and resists immunotherapy. Here, using a preclinical pancreatic cancer murine model, we demonstrate a progressive decrease in IFNγ and Granzyme B and a concomitant increase in Tox and IL-10 in intratumoral tumor-specific T cells. Intratumoral myeloid cells produced elevated IL-27, a cytokine that correlates with poor patient outcome. Abrogating IL-27 signaling significantly decreased intratumoral Tox+ T cells and delayed tumor growth yet was not curative. Agonistic αCD40 decreased intratumoral IL-27producing myeloid cells, decreased IL-10-producing intratumoral T cells, and promoted intratumoral Klrg1+Gzmb+ short-lived effector T cells. Combination agonistic αCD40+αPD-L1 cured 63% of tumor-bearing animals, promoted rejection following tumor re-challenge and correlated with a 2-log increase in pancreas-residing tumor-specific T cells. Interfering with Ifngr1 expression in non-tumor/host cells abrogated agonistic αCD40+αPD-L1 efficacy. In contrast, interfering with non-tumor/host cell Tnfrsf1a led to cure in 100% of animals following agonistic αCD40+αPD-L1 and promoted the formation of circulating central memory T cells rather than