The adaptability of immune resistance in tumor locations

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The adaptability of immune resistance in tumor locations

The adaptability of immune resistance in tumor locations

The immune response can recognize, respond to, and eliminate cancer cells. However, during the progression of cancer, various cellular and molecular mechanisms undergo changes, especially in the tumor site, to adapt to alterations in the immune environment.

Ultimately, these changes enable cancer cells to overcome immune attacks, allowing them to persistently grow.

Collectively known as “Adaptive Immune Resistance” (AIR), this phenomenon results from the prolonged adaptation of cancer cells, leading to significant heterogeneity in human cancers of different or even the same pathological types.

The first clearly identified and therapeutically validated AIR is the Programmed Cell Death Ligand 1 (PD-L1).

The PD-1/PD-L1 pathway plays a major role in evading immune responses against tumors and is a key mechanism of AIR. Immune therapies based on PD-1/PD-L1 blockade have been successfully applied in clinical patients.

Since the approval of pembrolizumab and nivolumab for advanced melanoma in 2014, the FDA has approved indications for PD-1/PD-L1 antibodies in over 20 solid tumors or hematologic malignancies.

Currently, the focus of tumor immunotherapy has shifted from monotherapy to combination therapies. However, many clinical trials combining anti-PD-1 treatments with other anti-cancer drugs lack strong mechanistic foundations, failing to determine synergistic or additive effects. Therefore, understanding the AIR mechanisms at the tumor site should be a key focus guiding future drug development.

The AIR Hypothesis

Studying human PD-L1 in both normal and cancer states reveals several important features of AIR.

Firstly, although PD-1 is widely expressed on T cells activated in blood and the tumor microenvironment (TME), there is no PD-L1 expression in the TME before T cells recognize and activate through antigen recognition.

This allows selective expression of PD-L1 in the TME. Additionally, some tumors express PD-L1 without apparent T cell infiltration. Secondly, PD-L1 expression can impair the immune function of the TME without the need for systemic immune suppression.

PD-L1 on tumor cells induces the death or dysfunction of activated T cells, leading to resistance to T cell-mediated destruction.

Thirdly, the PD-1/PD-L1 pathway appears to be a major AIR mechanism in some late-stage cancer patients, and monotherapy with anti-PD-1/PD-L1 treatments can be effective in these cases.

AIR mechanisms differ from general immune suppression mechanisms such as CTLA-4 receptor-mediated mechanisms. CTLA-4 mainly suppresses the inherent self-reactivity of healthy individuals by regulating regulatory T (Treg) cells. Another example is Transforming Growth Factor-β (TGF-β), which, in addition to suppressing unnecessary inflammation and autoimmunity, has widespread roles in normal homeostasis mechanisms, including wound healing, blood vessel formation, and cell growth.

In addition to the PD1/PD-L1 pathway, other AIR mechanisms exist in the TME, such as Siglec-15, which is upregulated mainly in myeloid cells and tumor cells in PD-L1-negative TME. Moreover, over half of human cancers are considered “cold tumors,” lacking apparent inflammation and immune responses in pathological analysis, and these tumors may also have unique AIR mechanisms. Therefore, late-stage cancers may use multiple AIR mechanisms simultaneously or sequentially to evade immune system attacks, and our understanding of AIR mechanisms is still in its early stages.

Classification of AIR

It is estimated that approximately 25% of solid tumor patients and 40-60% of lymphoma patients respond to current anti-PD-1/PD-L1 treatments. However, the objective response rate (ORR) varies significantly among different cancer types.

For example, Merkel cell carcinoma and advanced melanoma have ORRs of 56% and 45%, respectively, while advanced non-small cell lung cancer has an ORR of about 20%, and gastroesophageal junction cancer has an ORR of only 16%.

Long-term survival studies in melanoma, renal cell carcinoma (RCC), and lung cancer suggest that the 5-year survival rate is directly related to a good ORR. Therefore, accurately determining which patients will or will not respond is crucial before initiating treatment.

Based on the tumor immune microenvironment (TIME), cancer can be classified into four different types to better define the immune status, predict tumor response, or assess resistance to anti-PD-1/PD-L1 treatments. This classification, based on early studies in human melanoma, categorizes tumors into four types: PD-L1-/TIL- (Type I); PD-L1+/TIL+ (Type II); PD-L1-/TIL+ (Type III); and PD-L1+/TIL- (Type IV).

The adaptability of immune resistance in tumor locations

Primary Resistance

Primary resistance to anti-PD therapy is defined as the initial lack of response in Type II tumors (PD-L1+/TIL+), which have PD-L1 expression and T cell infiltration. Therefore, these tumors are expected to respond to anti-PD therapy. However, the presence of TIL, especially CD8+ T cells, has not been used as a predictive biomarker for patient selection. Thus, PD-L1+ tumors actually encompass both AIR types II and IV. Since Type IV tumors lack T cell infiltration, it is expected that they will not respond to anti-PD therapy solely based on PD-L1 positivity.

Additionally, PD-L1 expression may be dynamic, as it is largely inducible and may differ from biopsy to the initiation of anti-PD therapy. Besides assessing PD-L1 expression, it is crucial to evaluate the expression of other co-inhibitory and co-stimulatory molecules to fully harness effective immune responses.

While the presence of TIL seems crucial, it is still unclear which key cellular components on TIL and molecular components on TIL determine primary resistance. The presence of CD8+ and T-helper 1 (TH1) cells in the TME is consistently associated with better prognosis and may be crucial cellular components preventing primary resistance. However, the roles of other TIL components, including CD4+ T cell subsets, natural killer (NK) cells, NKT cells, B cells, Treg cells, γδ T cells, and innate lymphoid cells in the TME, remain unclear. Additionally, the presence of Treg cells and myeloid-derived suppressor cells (MDSCs) may positively regulate primary resistance. Comprehensive analysis of cells and molecules in TIME type II can help identify high-risk patients for primary resistance to anti-PD therapy.

Acquired Resistance

Among metastatic melanoma patients who initially responded to anti-PD therapy, approximately 1/4 to 1/3 experience recurrence over time, a phenomenon also observed in lung cancer. Therefore, these patients develop acquired resistance to anti-PD therapy. Currently, there are no clear biomarkers or clinical standards to predict recurrence, posing a pressing challenge in clinical practice.

Clinical observations provide some clues to the potential mechanisms of acquired resistance. PD-L1 and PD-1 expression remains positive in patients with acquired resistance, indicating an activated phenotype of infiltrated T cells. Interestingly, in some cases, patients who relapsed after a period of treatment cessation or chemotherapy can regain responsiveness to anti-PD therapy. In these cases, acquired resistance cannot be explained by tumor antigen mutations or losses. However, intrinsic changes in tumor cells may occur, reducing sensitivity to immune attacks.

In a small subset of relapsed patients, functional loss mutations are associated with acquired resistance, such as functional loss mutations in JAK1 and JAK2, as well as truncation mutations in the β2-microglobulin (B2M) gene. These mutations are related to adverse reactions to anti-PD therapy because interferon signaling-mediated cancer cell death requires JAK pathway activation, and B2M mutations reduce the expression of major histocompatibility complex (MHC) class I. Overall, although reports on the functional loss of immune-related molecules provide reasonable examples of acquired resistance or even primary resistance, the frequency of these events is low, and causation is still to be established.

Target Loss Resistance

Since anti-PD therapy works by blocking the interaction between PD-1 and PD-L1, tumors lacking their expression in the TME theoretically do not allow this treatment to be effective. Tumors lacking PD-1 or PD-L1 expression are classified as “target loss.” Therefore, it is not surprising to observe poorer responses to anti-PD therapy in patients with AIR Types I, III, and IV. Target loss resistance occurs in 60–85% of solid tumors. This is why only a small subset of patients responds to anti-PD therapy.

A common feature of AIR Types I and IV is the lack of TIL. In the absence of T cell infiltration, PD-L1 expression through AIR Type IV is unlikely to be induced by TIL interferons. Constitutive expression of PD-L1 is known to be associated with genetic amplification of chromosome 9p24.1, leading to overexpression of PD-L1, PD-L2, and Janus kinase 2 (JAK2). In the absence of immune infiltration, other mechanisms leading to constitutive expression of PD-L1 on cancer cells include PTEN loss or mutations in PI3K and/or AKT, EGFR mutations, MYC overexpression, CKD5 disruption, among others. These findings at least partially explain why some PD-L1+ tumor patients do not respond to anti-PD therapy.

Conclusion

Anti-PD therapy indicates that selectively blocking treatments for tumor-induced AIR mechanisms is effective for cancer patients.

However, in-depth analysis of the human TME reveals that, in addition to the PD pathway, there are other highly complex and heterogeneous AIR mechanisms.

What we currently see may only be the tip of the iceberg.

Therefore, further identification of several major AIR mechanisms operating in the TME, understanding and targeting these new mechanisms, will help effectively treat a larger proportion of human cancer patients in the near future.