Jason M. Link, Ph.D., Department of Molecular and Medical Genetics, Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University Tumor-Infiltrating Leukocyte Phenotypes Distinguish Outcomes in Related Patients With Pancreatic Adenocarcinoma.
Link to Case Report –
https://ascopubs.org/doi/full/10.1200/PO.20.00287
One of the greatest mortality risks of all cancers includes pancreatic ductal adenocarcinoma (PDAC). Most patients have either metastatic PDAC (50 percent -60 percent) or locally advanced tumors (30 percent -40 percent), for which the median survival after diagnosis is 5-9 months. Oh, 1,2 For the limited subset (10 percent -20 percent) of patients who present with resectable tumors confined to the pancreas, outcomes are still suboptimal; < 50 percent of these patients, despite modern adjuvant chemotherapy, live 5 years after surgery. 3 In addition, in the autopsy, 88% of recurrences of the disease are metastatic and >80% have more than 10 distinct metastatic lesions4 that are genetically linked to the primary tumor5 and other metastases. 6 These results suggest that the majority of PDAC patients have non-radiographically clear, post-resection micrometastatic disease and that residual tumor cells evade or develop resistance to adjuvant chemotherapy. Though tropism to specific organs is still poorly understood during metastatic spread, patients with liver or peritoneum recurrence7 survive significantly shorter than patients with recurrent lung metastases.
Two major subtypes are generally known as PDAC tumors: one that shares certain characteristics with adenosquamous tumors (squamoid and/or basal) and the other that preserves a differentiated (ductal and/or classical) glandular and/or ductal morphology. Squamoid PDAC tumors are more glycolytic,11,12 are more hypoxic,13 are more likely to metastasize,14,15 are more likely to recruit inflammatory fibroblasts,16 have a worse prognosis than ductal tumors. Seventeen-21 More tumor-infiltrating leukocytes, denser collagen, and better results are associated with classical subtype tumors15,22, although substantial subtype heterogeneity within tumors13 complicates the relationship between subtype and outcome.
More cytolytic T cells than most other tumors invade PDAC tumors,23 but are ultimately ineffective to manage cancer. Among PDAC tumors, tumor-infiltrating T cell density is highly variable,24 and abundant CD8+ T cells (along with a high number of neoantigens) can exceptionally support long-term survival. 25 T cell-mediated tumor immunity can, however, be limited by several mechanisms: downregulation of HLA by tumor cells, immunosuppressive leukocytes, the proximity of T cells to tumor cells, and exhaustion of T cells. 26 to 30 A high diversity of functional T cell clones, tumor-specific recruitment of effector T cells, and abundant neoantigens improve efficient T cell-mediated tumor immunity. 23,25,31" It is essential to quantify leukocyte phenotypes, functions, and locations in order to recognize precise tumor immunity necessary for exceptional positive results.
Equally unusual, idiosyncratic patient genetics, tumor-specific somatic alterations, and gene expression, and/or stochastically generated tumor immunity can mediate rare, exceptional control of PDAC progression. This study describes the cases of Pt1, who lived for more than 46 months with occult metastatic PDAC resistant to chemotherapy, and her niece (Pt2) who, through intensive treatment, succumbed to progressive metastatic disease. These two patients compare clinical outcomes and primary and metastatic tumors, finding significant variations in the subtype, somatic changes, and leukocyte lineages that may have contributed to divergent disease courses in some combination or alone.