VSIR and neoplasm: Extrinsic factors such as the absence of T cells, inhibitory immune checkpoints (VISTA, LAG-3, TIM-3), immunosuppressive cells (myeloid-derived suppressor cells [MDSCs], Tregs, or type II macrophages), and abnormal tumor extracellular matrix (ECM; abnormal tumor vessel and fibrotic collagen) can create an immunosuppressive environment 13, 15, 17, 18.