Classic Hodgkin Lymphoma Beyond the Lymph Node: A Systemic Immunobiological Paradigm
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe topic and overall concept of this review are very interesting, and shifting the focus from the local lymph node environment to a more systemic perspective is potentially valuable for the field. However, the manuscript reads more as a descriptive summary of existing studies. Providing more critical discussion would substantially strengthen the manuscript and better support the scope suggested by the title.
- 9p24.1 amplification commonly results in concurrent overexpression of PD-L1, PD-L2, and JAK2 in cHL. As JAK2 signaling can further enhance PD-L1 expression, it would be helpful to include the overexpression of JAK2 as part of 9p24.1 amplification.
- After introducing PD-L1 and PD-L2, it may be clearer to also briefly discuss PD-1 expression on TILs to provide a more complete immunological background.
- In addition to 9p24.1 amplification, SOCS1 is frequently mutated in HRS cells and likely plays an important role in immune evasion. Including this aspect would strength the discussion.
- The HRS cells recruit more than just the cells currently mentioned. Cell types such as eosinophils and mast cells are also commonly described in cHL TME studies. Including these populations would provide a more complete picture of the microenvironment.
- The role of EBV should also be included in the main text, especially since EBV-associated LMP1 can activate JAK/STAT and NF-κB signaling pathways in a subset of cHL cases.
- It would be helpful to specify the key cytokines and chemokines responsible for the recruitment of immune cells.
- Section numbering may need minor revision. For example, Section 3.1 contains only a single subsection (3.1.1), as does Section 3.2.
Author Response
Response to Reviewer 1
We thank the Reviewer for the positive overall assessment and for the insightful suggestions. We have addressed all points as detailed below.
Reviewer 1 – Comment 1
“9p24.1 amplification commonly results in concurrent overexpression of PD-L1, PD-L2, and JAK2 in cHL. As JAK2 signaling can further enhance PD-L1 expression, it would be helpful to include the overexpression of JAK2 as part of 9p24.1 amplification.”
Response:
We agree and have now explicitly described the concurrent overexpression of JAK2 resulting from 9p24.1 amplification, and its contribution to enhanced PD-L1 expression via JAK/STAT signaling.
Change in manuscript:
A sentence has been added in the section on genetic drivers of immune evasion:
“The 9p24.1 amplicon includes JAK2 in addition to PD-L1 and PD-L2, and JAK2 overexpression further augments PD-L1 transcription through constitutive activation of JAK/STAT signaling.”
Reviewer 1 – Comment 2
“After introducing PD-L1 and PD-L2, it may be clearer to also briefly discuss PD-1 expression on TILs.”
Response:
We have added a short paragraph clarifying PD-1 expression on tumor-infiltrating lymphocytes (TILs), as this is crucial to understanding the effectiveness of PD-1 blockade in cHL.
Change in manuscript:
Inserted text:
“PD-1 is highly expressed on tumor-infiltrating CD4+ and CD8+ T cells in cHL, reflecting chronic antigenic stimulation and functional exhaustion. This sets the basis for the profound clinical activity of PD-1 blockade in this disease.”
Reviewer 1 – Comment 3
“SOCS1 is frequently mutated in HRS cells and likely plays an important role in immune evasion.”
Response:
We agree and have added SOCS1 alterations as an additional mechanism contributing to deregulated JAK/STAT signaling and immune escape.
Change in manuscript:
Added:
“Loss-of-function mutations in SOCS1, a negative regulator of JAK/STAT signaling, further potentiate STAT hyperactivation in a substantial subset of cHL cases, reinforcing PD-L1 upregulation and immune evasion.”
Reviewer 1 – Comment 4
“The HRS cells recruit more than just the cells currently mentioned—eosinophils and mast cells are also common. Include these populations.”
Response:
We have expanded the description of the TME by including eosinophils and mast cells, both well-recognized components of the cHL microenvironment.
Change in manuscript:
Added to the TME section:
“In addition to lymphoid and myeloid subsets, eosinophils and mast cells are frequently enriched in the cHL microenvironment. These populations are recruited through cytokines such as IL-5 and CCL5 and contribute to tissue remodeling, angiogenesis, and support of HRS cell survival.”
Reviewer 1 – Comment 5
“The role of EBV should also be included, especially since LMP1 activates JAK/STAT and NF-κB.”
Response:
We have added a paragraph summarizing the role of EBV-driven signaling in a subset of HL, including LMP1-mediated activation of NF-κB and JAK/STAT pathways.
Change in manuscript:
Added:
“EBV-positive cHL, particularly in mixed cellularity cases, displays expression of LMP1, which constitutively activates NF-κB and JAK/STAT signaling. This viral program contributes to immune evasion, cytokine production, and enhanced PD-L1 expression.”
Reviewer 1 – Comment 6
“Specify the key cytokines and chemokines responsible for recruitment of immune cells.”
Response:
We have expanded the cytokine/chemokine description and included representative molecules (e.g., CCL17, CCL22, IL-5, CCL5).
Change in manuscript:
Inserted text describing main mediators of immune-cell recruitment:
“HRS cells secrete a broad array of chemokines, including TARC/CCL17 and CCL22 (attracting CCR4+ Th2 and Treg cells), CCL5 (recruiting eosinophils and mast cells), and cytokines such as IL-5 and IL-13, which orchestrate the characteristic Th2-skewed and immunosuppressive TME.”
Reviewer 1 – Comment 7
“Section numbering may need minor revision (e.g., single-item subsections).”
Response:
The section numbering has been revised for clarity and to avoid isolated subsections.
Change in manuscript:
Updated section 3.1 and 3.2 to eliminate single-item subdivisions.
Reviewer 2 Report
Comments and Suggestions for AuthorsI believe the manuscript is timely, conceptually coherent, and clinically relevant, especially given the growing role of immune checkpoint blockade in cHL and the rising interest in ctDNA-based response assessment. However, I have some minor concerns as follows:
1. There is no brief description of how the literature was identified/selected. For a paradigm-shifting review, even a short “methods/search approach” paragraph would increase credibility.
2. Some claims (especially around ctDNA “outperforming imaging” and the readiness of peripheral immune profiling for routine stratification) would benefit from more cautious wording and explicit labeling as emerging/in-development.
3. The paper proposes a multidimensional framework but does not clearly address practical issues (assay standardization, thresholds, timing of ctDNA sampling, integration into PET-adapted algorithms).
Author Response
Response to Reviewer 2
We thank the reviewer for the positive and supportive comments and have addressed all suggestions below.
Reviewer 2 – Comment 1
“There is no brief description of how the literature was identified/selected.”
Response:
We have added a concise paragraph describing our search strategy, databases consulted, and inclusion criteria.
Change in manuscript:
A short “Literature Search Approach” paragraph has been added to the Introduction:
“Relevant literature was identified through PubMed and Web of Science searches (last updated January 2026) using terms related to ‘Hodgkin lymphoma’, ‘tumor microenvironment’, ‘immune evasion’, ‘ctDNA’, and ‘immune profiling’. We prioritized peer-reviewed original studies and high-quality reviews focusing on biological and systemic aspects of cHL. Additionally, this review integrates knowledge and findings from the authors' own research experience, supported by extensive engagement with current oncology literature.”
Reviewer 2 – Comment 2
“Some claims (ctDNA outperforming imaging, readiness of immune profiling for routine use) should be more cautious and labeled as emerging.”
Response:
We agree and have softened statements accordingly. All references to ctDNA superiority over imaging have been rephrased to emphasize emerging evidence, early data, or ongoing validation. The description of peripheral immune profiling was also reframed as promising but not yet standardized.
Change in manuscript:
Revisions include phrases such as:
“Early studies suggest that ctDNA may provide complementary or potentially more sensitive early response information compared with interim PET, although systematic validation is ongoing.”
and
“Peripheral immune profiling is a promising investigational tool but currently lacks standardized assays, reference ranges, and validated clinical thresholds.”
Reviewer 2 – Comment 3
“The framework does not clearly address practical issues (assay standardization, thresholds, timing, integration with PET).”
Response:
We have expanded the Discussion to address practical considerations for clinical implementation, including timing of ctDNA collection, lack of assay harmonization, challenges in defining universal thresholds, and strategies for integrating molecular monitoring with PET-adapted therapy.
Change in manuscript:
A new paragraph has been added to the “Therapeutic Implications / Monitoring Framework” section:
“Several practical considerations need to be addressed before multidimensional monitoring can be broadly adopted, including harmonization of ctDNA sequencing assays, definition of clinically meaningful thresholds, optimal timing of sampling relative to treatment cycles, and integration with established PET-adapted algorithms. Prospective trials incorporating standardized ctDNA collection and paired imaging will be essential to validate these approaches.”
