There is an increasing awareness of the mechanisms whereby cancer evades the immune recognition by the host. Cancer cells induce an immune suppressive microenvironment and during the previous CRC grant period, we have made considerable progress using CLL as a model to understand how cancer cells alter T cell, NK cell, and myeloid/macrophage cell function. 

CLL cells hamper tumor-specific responses by dysregulating activation events in tumor infiltrating lymphocytes. We have found that the increased expression of CD274 (PDL1) on CLL cells increases PD1 on T cells and impairs T cell responses. This effect causes the host immune response to provide instead a microenvironment conducive to supporting leukemic cell growth. The CRC program has enabled us to study the altered gene expression profiles in T cells, NK cells, and macrophages in CLL and other malignancies. In addition, we have discovered that the inhibitory molecules CD274(PDL1), CD200 (OX2), CD270 (HVEM) and CD276 (B7-H3), expressed on CLL cells, induce altered actin polymerization and T cell exhaustion. We have also used the well-characterized Eμ-TCL1 mouse model, developed from Dr. Croce’s lab (Project 1 of the CRC), to demonstrate that the PDL1 blockade prevents T cell and myeloid-derived suppressor cell changes and this alone is sufficient to alter the disease course in CLL.

These discoveries have provided a strong scientific rationale for clinical trials of checkpoint inhibition. We hypothesize that the genetic events that are recurrently acquired in CLL enhance CLL fitness and that this works in part through the alteration of the tumor microenvironment and that CLL progression is matched by the progressive change in host immunity. 

We now seek to understand the molecular mechanisms whereby CLL cells increase expression of inhibitory ligands and are impacted by altered miRNA (in collaborations with Dr. Croce’s lab Project 1)genetic changes and increasing clonal diversity (with Project 2), expression of ROR1 (with Project 3). We propose that CLL, with its dependence on the microenvironment, is an ideal model disease to address this hypothesis providing access to tissue compartments blood, bone marrow and lymph node (LN) that harbor both leukemic cells and host immune elements.