Classification of Advanced Human Cancers Based on Tumor Immunity in the MicroEnvironment (TIME) for Cancer Immunotherapy

Abstract

sify TIME are done at the time of diagnosis but rarely are repeated at the time of progression. While the TIME classification is important in helping with the selection of therapy at the time of biopsy, defining the TIME will require repeated biopsies. Cancer immunology is a complex dynamic arena, in which a multitude of factors are at play in the same tumor, and at the same time, and can change with treatments or over time. Additional characteristics can be built into this model in the future to further help characterize tumor immune responses as we enter the golden age of cancer immunotherapy.

The Challenge for Development of Valuable Immuno-oncology Biomarkers

“…In dissecting the tumor microenvironment to understand which tumors may be most responsive to immunotherapy, the “Tumor-Immune Microenvironment (TIME)” classification system, developed by Zhang and Chen is helpful (28). This system builds upon prior classifications of tumors as T-cell inflamed, infiltrated with T lymphocytes and an interferon signature that may be primed for response to immunotherapy, versus non-inflamed tumors that lack robust T cell infiltration and are more resistant to immune approaches (17,29,30).…”

“…This system builds upon prior classifications of tumors as T-cell inflamed, infiltrated with T lymphocytes and an interferon signature that may be primed for response to immunotherapy, versus non-inflamed tumors that lack robust T cell infiltration and are more resistant to immune approaches (17,29,30). TIME recognizes 4 separate phenotypes within the TME -- T1 (B7-H1 − , TIL − ), T2 (B7-H1 + , TIL + ), T3 (B7-H1 − , TIL + ), and T4 (B7-H1 + , TIL − ) -- that segregate tumors that are responsive from those that are resistant to checkpoint blockade; see Figure 2 (modelled after the figure in (28) for an illustration of these phenotypes). T2 tumors, which typically contain TILs and other immune cells, but are resistant to cell-killing by TILs due to B7-H1 expression, are thought to account for most anti-PD-1 responses.…”

“…This figure, modelled after Zhang and Chen’s (28), illustrates the four tumor subtypes of TIME; T1-T4.…”

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

“…Another emerging combinatorial approach involves epigenetic therapies with in vivo demonstration of synergy; growing evidence indicates that epigenetic reprogramming may suppress immune-related genes and/or tumor-specific antigens (30). An alternative pragmatic classification model stratifies the TME into four types based on the presence or absence of tumor-infiltrating lymphocytes and PD-L1 expression (31, 32). However, caveats include the lack of standardized methodology and sampling challenges in light of intratumoral heterogeneity and the adaptive and dynamic nature of immune resistance.…”

“…For example, the aforementioned stratification of the TME based on PD-L1 status and lymphocytic infiltration has been described to guide treatment options (32, 83). Although several groups found tumor mutational burden and neoantigen load were positively associated with immune checkpoint inhibitor response, there was overlap in the range of mutations and neoantigens between the responders and nonresponders (84, 85).…”